European Journal of Clinical Investigation最新文献

{"title":"Exploring omics signature in the cardiovascular response to semaglutide: Mechanistic insights and clinical implications","authors":"Rui Vitorino","doi":"10.1111/eci.14334","DOIUrl":"10.1111/eci.14334","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, is a widely used drug for the treatment of type 2 diabetes that offers significant cardiovascular benefits.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>This review systematically examines the proteomic and metabolomic indicators associated with the cardiovascular effects of semaglutide. A comprehensive literature search was conducted to identify relevant studies. The review utilizes advanced analytical technologies such as mass spectrometry and nuclear magnetic resonance (NMR) to investigate the molecular mechanisms underlying the effects of semaglutide on insulin secretion, weight control, anti-inflammatory activities and lipid metabolism. These “omics” approaches offer critical insights into metabolic changes associated with cardiovascular health. However, challenges remain such as individual variability in expression, the need for comprehensive validation and the integration of these data with clinical parameters. These issues need to be addressed through further research to refine these indicators and increase their clinical utility.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Future integration of proteomic and metabolomic data with artificial intelligence (AI) promises to improve prediction and monitoring of cardiovascular outcomes and may enable more accurate and effective management of cardiovascular health in patients with type 2 diabetes. This review highlights the transformative potential of integrating proteomics, metabolomics and AI to advance cardiovascular medicine and improve patient outcomes.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12013,"journal":{"name":"European Journal of Clinical Investigation","volume":"55 2","pages":""},"PeriodicalIF":4.4,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142461195","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sodium-glucose co-transporter 2 inhibitors for all-cause and cardiovascular death in people with different stages of CKD: A systematic review and meta-analysis","authors":"Artemios G. Karagiannidis,&nbsp;Marieta P. Theodorakopoulou,&nbsp;Maria-Eleni Alexandrou,&nbsp;Fotini Iatridi,&nbsp;Eleni Karkamani,&nbsp;Vasileios Anastasiou,&nbsp;Ioannis Mykoniatis,&nbsp;Vasileios Kamperidis,&nbsp;Giovanni Strippoli,&nbsp;Pantelis Sarafidis","doi":"10.1111/eci.14335","DOIUrl":"10.1111/eci.14335","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Sodium-glucose co-transporter-2 inhibitors (SGLT2is) reduce cardiovascular risk in people with diabetes and established cardiovascular disease, but emerging studies in chronic kidney disease (CKD) have inconsistent results. In this systematic review, we evaluate the effects of SGLT2is on cardiovascular mortality in people with CKD as a whole and across subgroups stratified by baseline kidney function and among people at low, moderate, high and very high risk according to KDIGO- CKD classification system.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Literature search was conducted in PubMed/MEDLINE, Cochrane/CENTRAL, Scopus and Web of Science up to 30 November 2023. We included randomized controlled trials assessing the effect of SGLT2is on cardiovascular mortality in people with CKD. Secondary outcomes included all-cause mortality and major adverse cardiac events (MACE).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Eleven studies (<i>n</i> = 83,203 participants) were included. In people with CKD, treatment with SGLT2is compared to placebo reduced the risk of cardiovascular death by 14% (hazard ratio [HR] .86; 95%CI .79–.94), all-cause death by 15% (HR .85; 95%CI .79–.91) and MACEs by 13% (HR .87; 95%CI .81–.93). A consistent treatment effect was observed across eGFR-subgroups (≥60 mL/min/1.73 m²: HR .82, 95%CI .65–1.02; &lt;60 mL/min/1.73 m²: HR .86, 95%CI .77–.96, <i>p</i>-subgroup difference = .68) and KDIGO risk-categories (low, moderate, high and very high) (<i>p</i>-subgroup difference = .69) for cardiovascular death; reduction in the risk of all-cause death tended to be greater in the highest KDIGO risk categories. A consistent treatment effect on cardiovascular mortality was observed for different SGLT2is agents studied. Sensitivity analysis for cardiovascular mortality endpoint including studies in diabetic people yielded similar results (HR .86; 95%CI .77–.97).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Treatment with SGLT2is led to a significant reduction in the risk of cardiovascular and all-cause mortality in people with different CKD stages. These findings support the use of SGLT2is as an adjunct cardiovascular protective therapy in CKD.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> PROSPERO Registration Number</h3>\u0000 \u0000 <p>PROSPERO registration number: CRD42022382863.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12013,"journal":{"name":"European Journal of Clinical Investigation","volume":"55 2","pages":""},"PeriodicalIF":4.4,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142461199","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cardiac troponin elevation and mortality in takotsubo syndrome: New insights from the international takotsubo registry","authors":"Barbara E. Stähli,&nbsp;Matthias Schindler,&nbsp;Victor Schweiger,&nbsp;Victoria L. Cammann,&nbsp;Konrad A. Szawan,&nbsp;David Niederseer,&nbsp;Michael Würdinger,&nbsp;Alexander Schönberger,&nbsp;Maximilian Schönberger,&nbsp;Iva Koleva,&nbsp;Julien C. Mercier,&nbsp;Vanya Petkova,&nbsp;Silvia Mayer,&nbsp;Rodolfo Citro,&nbsp;Carmine Vecchione,&nbsp;Eduardo Bossone,&nbsp;Sebastiano Gili,&nbsp;Michael Neuhaus,&nbsp;Jennifer Franke,&nbsp;Benjamin Meder,&nbsp;Miłosz Jaguszewski,&nbsp;Michel Noutsias,&nbsp;Maike Knorr,&nbsp;Thomas Jansen,&nbsp;Fabrizio D’Ascenzo,&nbsp;Wolfgang Dichtl,&nbsp;Dirk von Lewinski,&nbsp;Christof Burgdorf,&nbsp;Behrouz Kherad,&nbsp;Carsten Tschöpe,&nbsp;Annahita Sarcon,&nbsp;Jerold Shinbane,&nbsp;Lawrence Rajan,&nbsp;Guido Michels,&nbsp;Roman Pfister,&nbsp;Alessandro Cuneo,&nbsp;Claudius Jacobshagen,&nbsp;Mahir Karakas,&nbsp;Wolfgang Koenig,&nbsp;Alexander Pott,&nbsp;Philippe Meyer,&nbsp;Marco Roffi,&nbsp;Adrian Banning,&nbsp;Mathias Wolfrum,&nbsp;Florim Cuculi,&nbsp;Richard Kobza,&nbsp;Thomas A. Fischer,&nbsp;Tuija Vasankari,&nbsp;K. E. Juhani Airaksinen,&nbsp;L. Christian Napp,&nbsp;Rafal Dworakowski,&nbsp;Philip MacCarthy,&nbsp;Christoph Kaiser,&nbsp;Stefan Osswald,&nbsp;Leonarda Galiuto,&nbsp;Christina Chan,&nbsp;Paul Bridgman,&nbsp;Daniel Beug,&nbsp;Clément Delmas,&nbsp;Olivier Lairez,&nbsp;Ekaterina Gilyarova,&nbsp;Alexandra Shilova,&nbsp;Mikhail Gilyarov,&nbsp;Ibrahim El-Battrawy,&nbsp;Ibrahim Akin,&nbsp;Karolina Poledniková,&nbsp;Petr Toušek,&nbsp;David E. Winchester,&nbsp;Michael Massoomi,&nbsp;Jan Galuszka,&nbsp;Christian Ukena,&nbsp;Gregor Poglajen,&nbsp;Pedro Carrilho-Ferreira,&nbsp;Christian Hauck,&nbsp;Carla Paolini,&nbsp;Claudio Bilato,&nbsp;Yoshio Kobayashi,&nbsp;Ken Kato,&nbsp;Iwao Ishibashi,&nbsp;Toshiharu Himi,&nbsp;Jehangir Din,&nbsp;Ali Al-Shammari,&nbsp;Abhiram Prasad,&nbsp;Charanjit S. Rihal,&nbsp;Kan Liu,&nbsp;P. Christian Schulze,&nbsp;Matteo Bianco,&nbsp;Lucas Jörg,&nbsp;Hans Rickli,&nbsp;Gonçalo Pestana,&nbsp;Thanh H. Nguyen,&nbsp;Michael Böhm,&nbsp;Lars S. Maier,&nbsp;Fausto J. Pinto,&nbsp;Petr Widimský,&nbsp;Stephan B. Felix,&nbsp;Ruediger C. Braun-Dullaeus,&nbsp;Wolfgang Rottbauer,&nbsp;Gerd Hasenfuß,&nbsp;Burkert M. Pieske,&nbsp;Heribert Schunkert,&nbsp;Monika Budnik,&nbsp;Grzegorz Opolski,&nbsp;Holger Thiele,&nbsp;Johann Bauersachs,&nbsp;John D. Horowitz,&nbsp;Carlo Di Mario,&nbsp;William Kong,&nbsp;Mayank Dalakoti,&nbsp;Yoichi Imori,&nbsp;Luca Liberale,&nbsp;Fabrizio Montecucco,&nbsp;Thomas Münzel,&nbsp;Filippo Crea,&nbsp;Thomas F. Lüscher,&nbsp;Jeroen J. Bax,&nbsp;Frank Ruschitzka,&nbsp;Jelena R. Ghadri,&nbsp;Davide Di Vece,&nbsp;Christian Templin","doi":"10.1111/eci.14317","DOIUrl":"10.1111/eci.14317","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>The clinical relevance of cardiac troponin (cTn) elevation in takotsubo syndrome (TTS) remains uncertain. The present study sought to investigate the role of cardiac troponin (cTn) elevations in mortality prediction of patients with Takotsubo syndrome (TTS).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Patients enrolled in the International Takotsubo (InterTAK) Registry from January 2011 to February 2020 with available data on peak cTn levels were included in the analysis. Peak cTn levels during the index hospitalization were used to define clinically relevant myocardial injury. The threshold at which clinically relevant myocardial injury drives mortality at 1 year was identified using restricted cubic spline analysis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Out of 2′938 patients, 222 (7.6%) patients died during 1-year follow-up. A more than 28.8-fold increase of cTn above the upper reference limit was identified as threshold for clinically relevant myocardial injury. The presence of clinically relevant myocardial injury was significantly associated with an increased risk of mortality at 5 years (adjusted HR 1.58, 95% CI 1.18–2.12, <i>p</i> =.002). Clinically relevant myocardial injury was related to an increased 5-year mortality risk in patients with apical TTS (adjusted HR 1.57, 95% CI 1.21–2.03, <i>p</i> =.001), in presence of physical stressors (adjusted HR 1.60, 95% CI 1.22–2.11, <i>p</i> =.001), and in absence of emotional stressors (adjusted HR 1.49, 95% CI, 1.17–1.89, <i>p</i> =.001).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>This study for the first time determined a troponin threshold for the identification of TTS patients at excess risk of mortality. These findings advance risk stratification in TTS and assist in identifying patients in need for close monitoring and follow-up.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12013,"journal":{"name":"European Journal of Clinical Investigation","volume":"54 12","pages":""},"PeriodicalIF":4.4,"publicationDate":"2024-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142461194","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Glucagon and glucagon-like peptide-1 dual agonist therapy: A possible future towards fatty kidney disease","authors":"Mehmet Kanbay,&nbsp;Sidar Copur,&nbsp;Mustafa Guldan,&nbsp;Lasin Ozbek,&nbsp;Francesca Mallamaci,&nbsp;Carmine Zoccali","doi":"10.1111/eci.14330","DOIUrl":"10.1111/eci.14330","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Obesity is a growing epidemic affecting approximately 40% of the adult population in developed countries with major health consequences and comorbidities, including diabetes mellitus and insulin resistance, metabolically associated fatty liver disease, atherosclerotic cardiovascular and cerebrovascular diseases and chronic kidney disease. Pharmacotherapies targeting significant weight reduction may have beneficial effects on such comorbidities, though such therapeutic options are highly limited. In this narrative review, we aim to evaluate current knowledge regarding dual agonist therapies and potential implications for managing fatty kidney and chronic kidney disease.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results and Conclusion</h3>\u0000 \u0000 <p>Glucagon-like peptide-1 agonists and sodium-glucose cotransporter-2 inhibitors are two novel classes of glucose-lowering medications with potential implications and beneficiary effects on renal outcomes, including estimated glomerular filtration rate, albuminuria and chronic kidney disease progression. Recently, dual agonist therapies targeting glucagon-like peptide-1 and glucagon receptors, namely survodutide and cotadutide, have been evaluated in managing metabolically associated fatty liver disease, a well-established example of visceral obesity. Fatty kidney is another novel concept implicated in the pathophysiology of chronic kidney disease among patients with visceral obesity.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12013,"journal":{"name":"European Journal of Clinical Investigation","volume":"55 1","pages":""},"PeriodicalIF":4.4,"publicationDate":"2024-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142461196","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Refining the role of presurgical PET/4D-CT in a large series of patients with primary hyperparathyroidism undergoing [18F]Fluorocholine PET/CT","authors":"Ashjan Kaseb,&nbsp;Houda Benider,&nbsp;Giorgio Treglia,&nbsp;Caterina Cusumano,&nbsp;Darejan Bessac,&nbsp;Pierpaolo Trimboli,&nbsp;Michel Vix,&nbsp;Arnoldo Piccardo,&nbsp;Adrien Latgé,&nbsp;Alessio Imperiale","doi":"10.1111/eci.14336","DOIUrl":"10.1111/eci.14336","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>4D-CT has garnered attention as complementary imaging for patients with primary hyperparathyroidism (pHPT). Herein we evaluated a diagnostic strategy using [¹⁸F]Fluorocholine Positron Emission Tomography/Computed Tomography (PET/CT), followed by 4D-CT integrated into PET/4D-CT after negative/inconclusive PET/CT results in a single-center retrospective cohort of 166 pHPT patients who underwent parathyroidectomy after [¹⁸F]Fluorocholine PET/4D-CT.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>PET/CT and 4D-CT images were interpreted by three nuclear medicine physicians and one expert radiologist. Pathological findings were documented, and concordance rates were assessed. PET/CT results were categorized as positive/negative, with positive cases rated on a 3-level certitude scale: low, moderate, high. Inconclusive cases included low/moderate positivity. The added value of PET/4D-CT was assessed for negative/inconclusive cases through joint reading.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>PET/CT lesion-based analysis showed almost perfect interobserver concordance (Cohen's kappa &gt;.8). Across the cohort, PET/CT had a sensitivity of 83%, specificity of 97%, PPV of 90% and NPV of 94%. For 4D-CT, these values were sensitivity: 53%, specificity: 84%, PPV: 56% and NPV: 82%. PET/CT was significantly more accurate than 4D-CT. Among 44 patients with negative/inconclusive results, PET/CT had sensitivity: 60%, specificity: 91%, PPV: 71% and NPV: 86%. In the same patients, sensitivity and specificity of the sequential diagnostic algorithm increased to 80% and 97%, showing significantly better global accuracy (92% vs. 83%) than standard PET/CT.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>We support a personalized imaging algorithm for pHPT, placing [¹⁸F]Fluorocholine PET/CT at the forefront, followed by 4D-CT integrated into PET/4D-CT in the same imaging session for negative/inconclusive results. When PET/CT results are clearly positive, the additional sensitivity benefit of 4D-CT is minimal.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12013,"journal":{"name":"European Journal of Clinical Investigation","volume":"55 2","pages":""},"PeriodicalIF":4.4,"publicationDate":"2024-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11744917/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142461198","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Efficacy and safety of benralizumab in eosinophilic granulomatosis with polyangiitis: A meta-analysis of eight studies","authors":"Federico Spataro,&nbsp;Antonio Giovanni Solimando,&nbsp;Attilio Di Girolamo,&nbsp;Angelo Vacca,&nbsp;Roberto Ria","doi":"10.1111/eci.14333","DOIUrl":"10.1111/eci.14333","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>Eosinophilic granulomatous polyangiitis (EGPA) is a rare autoimmune disease characterized by multisystemic inflammation, with eosinophils playing a central role in its pathogenesis. Traditional management relies heavily on corticosteroids and immunosuppressants, which are associated with significant side effects. The emergence of biologic agents, such as benralizumab, offers targeted therapeutic options by inhibiting the interleukin-5 receptor α, thereby reducing eosinophilic inflammation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This systematic review and meta-analysis comprehensively evaluate the efficacy and safety of benralizumab in EGPA patients, focusing on its ability to reduce oral corticosteroid (OCS) use, facilitate remission and spare immunosuppressants. We searched MEDLINE, LILACS and ISI Web of Science databases for relevant studies up to July 2024.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Eight studies, including both randomized controlled trials (RCTs) and observational studies, were included in the meta-analysis, involving a total of 396 EGPA patients. The pooled analysis demonstrated a significant reduction in OCS dose, with an overall estimated effect of −8.25 mg/day (95% CI, −9.39 to −7.10). Complete remission was achieved in 56.8% of patients, and immunosuppressants were reduced or discontinued in 28.1% of cases. Adverse events (AEs) were reported in 21.9% of patients, with only one discontinuation due to an AE.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>These findings provide robust evidence supporting the use of benralizumab as an effective and well-tolerated treatment option for EGPA, significantly reducing OCS requirements and offering promising remission rates. Future research should focus on larger, multicentre RCTs to confirm these findings and further elucidate the long-term benefits and safety profile of benralizumab in EGPA.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12013,"journal":{"name":"European Journal of Clinical Investigation","volume":"55 2","pages":""},"PeriodicalIF":4.4,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142389103","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Modulation of mitochondrial permeability transition pores in reperfusion injury: Mechanisms and therapeutic approaches","authors":"Giampaolo Morciano,&nbsp;Paolo Pinton","doi":"10.1111/eci.14331","DOIUrl":"10.1111/eci.14331","url":null,"abstract":"<p>Ischemia/reperfusion injury is attracting continuous interest in science for two reasons: because it affects several clinical conditions and because it has been identified, albeit in broad terms, the molecular entity becoming activated by the reperfusion damage paradoxes. Indeed, calcium, oxygen-dependent oxidative stress and pH would activate conformational changes in the mitochondrial cristae embedded F₁/F_O ATP synthase, allowing the formation of pores in the inner mitochondrial membrane thus increasing its permeability. This is a key determinant for mitochondrial stress, cell death and tissue dysfunction. Targeting each of these factors has never contributed to improved clinical outcome of the patients affected by reperfusion damage; now, the focus on the PTP opening could represent the closest target to solve this pathway made by extensive cell death when the tissues become revascularized. In this review, we summarized last knowledge about the structure, the modulation and the therapeutic targeting of the PTP, focusing on ATP synthase and cardiac ischemia/reperfusion.</p>","PeriodicalId":12013,"journal":{"name":"European Journal of Clinical Investigation","volume":"55 1","pages":""},"PeriodicalIF":4.4,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11628652/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142389104","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A newly developed, easy-to-use prehospital drug-derived score compared with three conventional scores: A prospective multicenter study","authors":"Jesús Jurado-Palomo,&nbsp;José Luis Martin-Conty,&nbsp;Begoña Polonio-López,&nbsp;Juan J. Bernal-Jiménez,&nbsp;Rosa Conty-Serrano,&nbsp;Michele Dileone,&nbsp;Miguel A. Castro Villamor,&nbsp;Carlos del Pozo Vegas,&nbsp;Raúl López-Izquierdo,&nbsp;Cristina Rivera-Picón,&nbsp;Francisco Martín-Rodríguez,&nbsp;Ancor Sanz-García","doi":"10.1111/eci.14329","DOIUrl":"10.1111/eci.14329","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Introduction</h3>\u0000 \u0000 <p>The use of medications by emergency medical services (EMS) is increasing. Conventional scores are time-consuming and therefore difficult to use in an emergency setting. For early decision-making, an easy-to-use score based on the medications administered by the EMS may have prognostic value. The primary objective of this study was to develop the prehospital drug-derived score (PDDS) for 2-day mortality.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A prospective, multicenter, ambulance-based cohort study was conducted in adults with undifferentiated acute diseases treated by EMS and transferred to the emergency department. Demographic data, prehospital diagnosis data, prehospital medication and variables for the calculation of the National Early Warning Score 2 (NEWS2), Rapid Emergency Medicine Score (REMS), and Rapid Acute Physiology Score (RAPS) were collected. The PDDS was developed and validated, establishing three levels of risk of 2-day mortality. The predictive capability of each score was determined by the area under the curve of the receiver operating characteristic curve (AUROC) and compared using the Delong's test (<i>p</i>-value).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>A total of 6401 patients were included. The PDDS included age and the use of norepinephrine, analgesics, neuromuscular blocking agents, diuretics, antihypertensive agents, tranexamic acid, and bicarbonate. The AUROC of PDDS was .86 (95% CI: .816–.903) versus NEWS2 .866 (95% CI: .822–.911), <i>p</i> = .828; versus REMS .885 (95% CI: .845–.924), <i>p</i> = .311; versus RAPS .886 (95% CI: .846–.926), <i>p</i> = .335, respectively.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>The newly developed easy-to-use prehospital drug-derived PDDS score has an excellent predictive value of early mortality. The PDDS score was comparable to the conventional risk scores and therefore might serve as an alternative score in the prehospital emergency setting.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12013,"journal":{"name":"European Journal of Clinical Investigation","volume":"55 1","pages":""},"PeriodicalIF":4.4,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11628643/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142380338","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ACKR3 agonism induces heterodimerization with chemokine receptor CXCR4 and attenuates platelet function","authors":"Valerie Dicenta-Baunach,&nbsp;Zoi Laspa,&nbsp;David Schaale,&nbsp;Manuel Sigle,&nbsp;Alp Bayrak,&nbsp;Tatsiana Castor,&nbsp;Thanigaimalai Pillaiyar,&nbsp;Stefan Laufer,&nbsp;Meinrad Paul Gawaz,&nbsp;Anne-Katrin Rohlfing","doi":"10.1111/eci.14327","DOIUrl":"10.1111/eci.14327","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Platelet receptors ACKR3 and CXCR4 play a crucial role in a variety of cardiovascular diseases. Like most chemokine receptors, CXCR4 is a G protein coupled receptor that induces platelet activation. In contrast, the atypical chemokine receptor 3 (ACKR3) lacks the ability to activate heterotrimeric G proteins and its activation leads to platelet inhibition and attenuates thrombus formation. In nucleated cells, heterodimerization of ACKR3 with CXCR4 regulates CXCL12-dependent signalling. The aim of our study was to investigate the formation of ACKR3/CXCR4 heterodimers in platelets and the subsequent consequences for platelet function.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods and Results</h3>\u0000 \u0000 <p>Using a proximity ligation assay (PLA, Duolink®) to screen for CXCR4/ACKR3 heterodimerization inducing compounds, we found that ACKR3 agonism but not conventional platelet agonists or endogen ligands lead to heterodimer formation. To further characterize the formation of ACKR3/CXCR4 heterodimers, we studied the CXCL12-dependent platelet activation via CXCR4. Both, CXCL12-dependent platelet aggregation and collagen-dependent ex vivo thrombus formation were significantly downregulated by ACKR3 agonism. Moreover, platelet intracellular calcium and Akt signalling were increased by CXCL12 and again suppressed by ACKR3-specific agonists. Previously, CXCL12 was shown to decrease platelet cAMP levels via CXCR4. Treatment with a specific ACKR3 agonist counteracted this CXCL12/CXCR4-dependent cAMP decrease.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Our results reveal that the formation of platelet ACKR3/CXCR4 heterodimers is dependent on ACKR3 rather than CXCR4. Furthermore, ACKR3 agonism induced heterodimerization is associated with mitigating CXCL12/CXCR4-dependent platelet activation possibly by modulating CXCR4-dependent G protein signalling. Our results indicate possible ACKR3 agonist functions and reinforce the potential therapeutic applications of ACKR3 agonists.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12013,"journal":{"name":"European Journal of Clinical Investigation","volume":"55 1","pages":""},"PeriodicalIF":4.4,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11628653/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142380339","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hypercholesterolemia and inflammation—Cooperative cardiovascular risk factors","authors":"Antonio Gallo,&nbsp;Wilfried Le Goff,&nbsp;Raul D. Santos,&nbsp;Isabella Fichtner,&nbsp;Stefano Carugo,&nbsp;Alberto Corsini,&nbsp;Cesare Sirtori,&nbsp;Massimiliano Ruscica","doi":"10.1111/eci.14326","DOIUrl":"10.1111/eci.14326","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Maintaining low concentrations of plasma low-density lipoprotein cholesterol (LDLc) over time decreases the number of LDL particles trapped within the artery wall, slows the progression of atherosclerosis and delays the age at which mature atherosclerotic plaques develop. This substantially reduces the lifetime risk of atherosclerotic cardiovascular disease (ASCVD) events. In this context, plaque development and vulnerability result not only from lipid accumulation but also from inflammation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Changes in the composition of immune cells, including macrophages, dendritic cells, T cells, B cells, mast cells and neutrophils, along with altered cytokine and chemokine release, disrupt the equilibrium between inflammation and anti-inflammatory mechanisms at plaque sites. Considering that it is not a competition between LDLc and inflammation, but instead that they are partners in crime, the present narrative review aims to give an overview of the main inflammatory molecular pathways linked to raised LDLc concentrations and to describe the impact of lipid-lowering approaches on the inflammatory and lipid burden. Although remarkable changes in LDLc are driven by the most recent lipid lowering combinations, the relative reduction in plasma C-reactive protein appears to be independent of the magnitude of LDLc lowering.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Identifying clinical biomarkers of inflammation (e.g. interleukin-6) and possible targets for therapy holds promise for monitoring and reducing the ASCVD burden in suitable patients.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12013,"journal":{"name":"European Journal of Clinical Investigation","volume":"55 1","pages":""},"PeriodicalIF":4.4,"publicationDate":"2024-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11628670/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142380340","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}