Shubham Soni, Rachel J Skow, Stephen Foulkes, Mark J Haykowsky, Jason R B Dyck
Recent evidence suggests that ketone bodies have therapeutic potential in many cardiovascular diseases including heart failure (HF). Accordingly, this has led to multiple clinical trials that use ketone esters to treat HF patients, which we term ketone therapy. Ketone esters, specifically ketone monoesters, are synthetic compounds which, when consumed, are de-esterified into two β-hydroxybutyrate (βOHB) molecules and increase the circulating βOHB concentration. While many studies have primarily focused on the cardiac benefits of ketone therapy in HF, ketones can have numerous favorable effects in other organs such as the vasculature and skeletal muscle. Importantly, vascular and skeletal muscle dysfunction are also heavily implicated in the reduced exercise tolerance, the hallmark feature in HF with reduced (HFrEF) and preserved (HFpEF) ejection fraction, suggesting that some of the benefits observed in HF in response to ketone therapy may involve these non-cardiac pathways. Thus, we review the evidence suggesting how ketone therapy may be beneficial in improving cardiovascular and skeletal muscle function in HF and identify various potential mechanisms that may be important in the beneficial non-cardiac effects of ketones in HF.
{"title":"Therapeutic potential of ketone bodies on exercise intolerance in heart failure: looking beyond the heart","authors":"Shubham Soni, Rachel J Skow, Stephen Foulkes, Mark J Haykowsky, Jason R B Dyck","doi":"10.1093/cvr/cvaf004","DOIUrl":"https://doi.org/10.1093/cvr/cvaf004","url":null,"abstract":"Recent evidence suggests that ketone bodies have therapeutic potential in many cardiovascular diseases including heart failure (HF). Accordingly, this has led to multiple clinical trials that use ketone esters to treat HF patients, which we term ketone therapy. Ketone esters, specifically ketone monoesters, are synthetic compounds which, when consumed, are de-esterified into two β-hydroxybutyrate (βOHB) molecules and increase the circulating βOHB concentration. While many studies have primarily focused on the cardiac benefits of ketone therapy in HF, ketones can have numerous favorable effects in other organs such as the vasculature and skeletal muscle. Importantly, vascular and skeletal muscle dysfunction are also heavily implicated in the reduced exercise tolerance, the hallmark feature in HF with reduced (HFrEF) and preserved (HFpEF) ejection fraction, suggesting that some of the benefits observed in HF in response to ketone therapy may involve these non-cardiac pathways. Thus, we review the evidence suggesting how ketone therapy may be beneficial in improving cardiovascular and skeletal muscle function in HF and identify various potential mechanisms that may be important in the beneficial non-cardiac effects of ketones in HF.","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"98 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142988651","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}
Ellen G Avery, Lea-Maxie Haag, Victoria McParland, Sarah M Kedziora, Gabriel J Zigra, Daniela S Valdes, Marieluise Kirchner, Oliver Popp, Sabrina Geisberger, Olivia Nonn, Tine V Karlsen, Gabriele N’Diaye, Alex Yarritu, Hendrik Bartolomaeus, Theda U P Bartolomaeus, Nurana A Tagiyeva, Moritz I Wimmer, Nadine Haase, Yiming D Zhang, Andreas Wilhelm, Gerald Grütz, Olav Tenstad, Nicola Wilck, Sofia K Forslund, Robert Klopfleisch, Anja A Kühl, Raja Atreya, Stefan Kempa, Philipp Mertins, Britta Siegmund, Helge Wiig, Dominik N Müller
Aims The gastrointestinal (GI) tract is composed of distinct sub-regions, which exhibit segment-specific differences in microbial colonization and (patho)physiological characteristics. Gut microbes can be collectively considered as an active endocrine organ. Microbes produce metabolites, which can be taken up by the host and can actively communicate with the immune cells in the gut lamina propria with consequences for cardiovascular health. Variation in bacterial load and composition along the GI tract may influence the mucosal microenvironment and thus be reflected its interstitial fluid (IF). Characterization of the segment-specific microenvironment is challenging and largely unexplored because of lack of available tools. Methods and results Here, we developed methods, namely tissue centrifugation and elution, to collect IF from the mucosa of different intestinal segments. These methods were first validated in rats and mice, and the tissue elution method was subsequently translated for use in humans. These new methods allowed us to quantify microbiota-derived metabolites, mucosa-derived cytokines, and proteins at their site-of-action. Quantification of short-chain fatty acids showed enrichment in the colonic IF. Metabolite and cytokine analyses revealed differential abundances within segments, often significantly increased compared to plasma, and proteomics revealed that proteins annotated to the extracellular phase were site-specifically identifiable in IF. Lipopolysaccharide injections in rats showed significantly higher ileal IL-1β levels in IF compared to the systemic circulation, suggesting the potential of local as well as systemic effect. Conclusion Collection of IF from defined segments and the direct measurement of mediators at the site-of-action in rodents and humans bypasses the limitations of indirect analysis of faecal samples or serum, providing direct insight into this understudied compartment.
{"title":"Intestinal interstitial fluid isolation provides novel insight into the human host-microbiome interface","authors":"Ellen G Avery, Lea-Maxie Haag, Victoria McParland, Sarah M Kedziora, Gabriel J Zigra, Daniela S Valdes, Marieluise Kirchner, Oliver Popp, Sabrina Geisberger, Olivia Nonn, Tine V Karlsen, Gabriele N’Diaye, Alex Yarritu, Hendrik Bartolomaeus, Theda U P Bartolomaeus, Nurana A Tagiyeva, Moritz I Wimmer, Nadine Haase, Yiming D Zhang, Andreas Wilhelm, Gerald Grütz, Olav Tenstad, Nicola Wilck, Sofia K Forslund, Robert Klopfleisch, Anja A Kühl, Raja Atreya, Stefan Kempa, Philipp Mertins, Britta Siegmund, Helge Wiig, Dominik N Müller","doi":"10.1093/cvr/cvae267","DOIUrl":"https://doi.org/10.1093/cvr/cvae267","url":null,"abstract":"Aims The gastrointestinal (GI) tract is composed of distinct sub-regions, which exhibit segment-specific differences in microbial colonization and (patho)physiological characteristics. Gut microbes can be collectively considered as an active endocrine organ. Microbes produce metabolites, which can be taken up by the host and can actively communicate with the immune cells in the gut lamina propria with consequences for cardiovascular health. Variation in bacterial load and composition along the GI tract may influence the mucosal microenvironment and thus be reflected its interstitial fluid (IF). Characterization of the segment-specific microenvironment is challenging and largely unexplored because of lack of available tools. Methods and results Here, we developed methods, namely tissue centrifugation and elution, to collect IF from the mucosa of different intestinal segments. These methods were first validated in rats and mice, and the tissue elution method was subsequently translated for use in humans. These new methods allowed us to quantify microbiota-derived metabolites, mucosa-derived cytokines, and proteins at their site-of-action. Quantification of short-chain fatty acids showed enrichment in the colonic IF. Metabolite and cytokine analyses revealed differential abundances within segments, often significantly increased compared to plasma, and proteomics revealed that proteins annotated to the extracellular phase were site-specifically identifiable in IF. Lipopolysaccharide injections in rats showed significantly higher ileal IL-1β levels in IF compared to the systemic circulation, suggesting the potential of local as well as systemic effect. Conclusion Collection of IF from defined segments and the direct measurement of mediators at the site-of-action in rodents and humans bypasses the limitations of indirect analysis of faecal samples or serum, providing direct insight into this understudied compartment.","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"28 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142968229","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}
Aims The therapeutic efficacy of coronary revascularization is compromised by myocardial ischemia-reperfusion (MI/R) injury. Higher levels of circulating arachidonic acid (AA) are reportedly associated with lower risk of cardiovascular disease. The cyclooxygenase (COX) pathway metabolizes AA into prostaglandins (PGs) and the platelet-activating thromboxane A2 (TXA2), which is inhibited by aspirin. We aimed to explore whether AA or its combination with aspirin modulates MI/R injury and aspirin-caused gastric bleeding. Methods and results Mice were subjected to 30min coronary artery ligation followed by reperfusion. AA reduced MI/R injury in mice, and its combination with aspirin provided further cardioprotection. Aspirin inhibited MI/R-triggered platelet activation and ameliorated microvascular obstruction immediately upon reperfusion, whereas AA improved microvascular perfusion at a later stage of reperfusion, coinciding with increased coronary vasodilatation. Co-administration of AA and aspirin markedly reduced cardiac neutrophil infiltration and vascular permeability and improved microcirculation. AA increased urinary metabolites of PGI2 and PGE2, not TXA2, and this selective augmentation was further enhanced by co-treatment with aspirin. Elevation in PGI2 and PGE2 correlated with reduced infarction and improved ventricular function, and inhibiting COX-2 attenuated the synergistic cadioprotection. Furthermore, oral administration of AA with aspirin after reperfusion provided a maximal cardioprotection and abolished aspirin-caused gastric bleeding. Conclusion AA synergizes with aspirin in protecting against MI/R injury, while minimizing the related bleeding risk, a major concern for patients with acute myocardial infarction. This is attributable to the selective augmentation of PGI2 and PGE2 that is amplified by TXA2 suppression by aspirin, underscoring improved microcirculation and ameliorated inflammation.
{"title":"Arachidonic acid synergizes with aspirin preventing myocardial ischemia-reperfusion injury and mitigates bleeding risk","authors":"Shaletanati Talabieke, Xuejian Yang, Jianfeng Yang, Qing Wan, Dekun Zhu, Haojie Rao, Yifei Wu, Zengrong Chen, Huihui Li, Pengfei Xu, Hong Chen, De-Pei Liu, Xu Zhang, Garret A FitzGerald, Miao Wang","doi":"10.1093/cvr/cvae254","DOIUrl":"https://doi.org/10.1093/cvr/cvae254","url":null,"abstract":"Aims The therapeutic efficacy of coronary revascularization is compromised by myocardial ischemia-reperfusion (MI/R) injury. Higher levels of circulating arachidonic acid (AA) are reportedly associated with lower risk of cardiovascular disease. The cyclooxygenase (COX) pathway metabolizes AA into prostaglandins (PGs) and the platelet-activating thromboxane A2 (TXA2), which is inhibited by aspirin. We aimed to explore whether AA or its combination with aspirin modulates MI/R injury and aspirin-caused gastric bleeding. Methods and results Mice were subjected to 30min coronary artery ligation followed by reperfusion. AA reduced MI/R injury in mice, and its combination with aspirin provided further cardioprotection. Aspirin inhibited MI/R-triggered platelet activation and ameliorated microvascular obstruction immediately upon reperfusion, whereas AA improved microvascular perfusion at a later stage of reperfusion, coinciding with increased coronary vasodilatation. Co-administration of AA and aspirin markedly reduced cardiac neutrophil infiltration and vascular permeability and improved microcirculation. AA increased urinary metabolites of PGI2 and PGE2, not TXA2, and this selective augmentation was further enhanced by co-treatment with aspirin. Elevation in PGI2 and PGE2 correlated with reduced infarction and improved ventricular function, and inhibiting COX-2 attenuated the synergistic cadioprotection. Furthermore, oral administration of AA with aspirin after reperfusion provided a maximal cardioprotection and abolished aspirin-caused gastric bleeding. Conclusion AA synergizes with aspirin in protecting against MI/R injury, while minimizing the related bleeding risk, a major concern for patients with acute myocardial infarction. This is attributable to the selective augmentation of PGI2 and PGE2 that is amplified by TXA2 suppression by aspirin, underscoring improved microcirculation and ameliorated inflammation.","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"30 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142936881","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":"Correction to: SerpinB1 targeting safeguards against pathological cardiac hypertrophy and remodelling by suppressing cardiomyocyte pyroptosis and inflammation initiation.","authors":"","doi":"10.1093/cvr/cvaf002","DOIUrl":"https://doi.org/10.1093/cvr/cvaf002","url":null,"abstract":"","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":""},"PeriodicalIF":10.2,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142945129","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":"RNA epigenetic modifications: a new field of research in calcific aortic valve disease.","authors":"Mewen Briend, Patrick Mathieu","doi":"10.1093/cvr/cvae256","DOIUrl":"https://doi.org/10.1093/cvr/cvae256","url":null,"abstract":"","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":""},"PeriodicalIF":10.2,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142945171","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":"Chemokine receptor-directed imaging, prognostication, and treatment of abdominal aortic aneurysm: can we do it all with CXCR4?","authors":"Martin Andreas, Irene M Lang","doi":"10.1093/cvr/cvae259","DOIUrl":"https://doi.org/10.1093/cvr/cvae259","url":null,"abstract":"","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":""},"PeriodicalIF":10.2,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142930716","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}
Gemma Vilahur, Soumaya Ben-Aicha, Manuel Gutiérrez, Monika Radike, Guiomar Mendieta, Lisaidy Ramos, Sebastia Alcover, Laura Casani, Gemma Arderiu, Teresa Padró, María Borrell, Lina Badimon
Aims Recurrent acute myocardial infarction (RE-AMI) is a frequent complication after STEMI, and its association with stent thrombosis can be life-threatening. Intravenous atorvastatin (IV-atorva) administration during AMI has been shown to limit infarct size and adverse cardiac remodeling. We determined by cardiac magnetic resonance (CMR) whether the cardioprotection exerted by IV-atorva at the index AMI event translates into a better prognosis upon RE-AMI in dyslipidemic pigs. Methods and Results Hypercholesterolemic pigs underwent a first AMI (90-minute coronary balloon occlusion). During ongoing ischemia, animals received IV-atorva or vehicle. Forty days later, animals underwent RE-AMI and were sacrificed on day43. All animals remained on p.o. atorvastatin and a high-cholesterol diet from the first AMI until sacrifice. Serial CMR analysis was performed on day3 post-AMI, prior- (day40) and post-RE-AMI (day43). No differences were detected in edema formation in both animal groups during AMI and RE-AMI. Gadolinium DE-CMR revealed smaller infarcts in IV-atorva-treated animals at index event at 3days and 40days post-AMI compared to vehicle-administered pigs (p<0.05). CMR analyses post-RE-AMI revealed smaller infarcts in the animals treated with IV-atorva at index event than in the vehicle-administered pigs. These IV-atorva at index event benefits were associated with higher LVEF and normal LV wall motion in the jeopardized myocardium at RE-AMI (p<0.05 vs. vehicle). The scar region of RE-AMI of animals treated with IV-atorva at index event showed reduced cardiac inflammatory infiltrate, apoptosis and senescence activation, and increased reparative fibrosis and neovessel formation vs. vehicle-administered pigs. Animals treated with IV-atorva at index event also showed lower CRP and higher IL-10 plasma levels in the setting of RE-AMI. Conclusions The cardioprotection afforded by IV-atorva administration during an index-AMI event shows a legacy effect attenuating myocardial damage and preserving cardiac contractile function upon RE-AMI. The potential benefits of this intravenous approach should be tested in the clinical setting.
{"title":"Cardioprotection exerted by intravenous statin at index myocardial infarction event attenuates cardiac damage upon recurrent infarction","authors":"Gemma Vilahur, Soumaya Ben-Aicha, Manuel Gutiérrez, Monika Radike, Guiomar Mendieta, Lisaidy Ramos, Sebastia Alcover, Laura Casani, Gemma Arderiu, Teresa Padró, María Borrell, Lina Badimon","doi":"10.1093/cvr/cvae264","DOIUrl":"https://doi.org/10.1093/cvr/cvae264","url":null,"abstract":"Aims Recurrent acute myocardial infarction (RE-AMI) is a frequent complication after STEMI, and its association with stent thrombosis can be life-threatening. Intravenous atorvastatin (IV-atorva) administration during AMI has been shown to limit infarct size and adverse cardiac remodeling. We determined by cardiac magnetic resonance (CMR) whether the cardioprotection exerted by IV-atorva at the index AMI event translates into a better prognosis upon RE-AMI in dyslipidemic pigs. Methods and Results Hypercholesterolemic pigs underwent a first AMI (90-minute coronary balloon occlusion). During ongoing ischemia, animals received IV-atorva or vehicle. Forty days later, animals underwent RE-AMI and were sacrificed on day43. All animals remained on p.o. atorvastatin and a high-cholesterol diet from the first AMI until sacrifice. Serial CMR analysis was performed on day3 post-AMI, prior- (day40) and post-RE-AMI (day43). No differences were detected in edema formation in both animal groups during AMI and RE-AMI. Gadolinium DE-CMR revealed smaller infarcts in IV-atorva-treated animals at index event at 3days and 40days post-AMI compared to vehicle-administered pigs (p&lt;0.05). CMR analyses post-RE-AMI revealed smaller infarcts in the animals treated with IV-atorva at index event than in the vehicle-administered pigs. These IV-atorva at index event benefits were associated with higher LVEF and normal LV wall motion in the jeopardized myocardium at RE-AMI (p&lt;0.05 vs. vehicle). The scar region of RE-AMI of animals treated with IV-atorva at index event showed reduced cardiac inflammatory infiltrate, apoptosis and senescence activation, and increased reparative fibrosis and neovessel formation vs. vehicle-administered pigs. Animals treated with IV-atorva at index event also showed lower CRP and higher IL-10 plasma levels in the setting of RE-AMI. Conclusions The cardioprotection afforded by IV-atorva administration during an index-AMI event shows a legacy effect attenuating myocardial damage and preserving cardiac contractile function upon RE-AMI. The potential benefits of this intravenous approach should be tested in the clinical setting.","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"2 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142929180","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":"Correction to: Patient-specific iPSC-derived cardiomyocytes reveal abnormal regulation of FGF16 in a familial atrial septal defect.","authors":"","doi":"10.1093/cvr/cvae227","DOIUrl":"10.1093/cvr/cvae227","url":null,"abstract":"","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":"2320"},"PeriodicalIF":10.2,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142562650","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}
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