Circulation最新文献

{"title":"Partial Heart Transplantation.","authors":"Taufiek K Rajab, Alekhya Mitta, Brian L Reemtsen","doi":"10.1161/CIRCULATIONAHA.124.071498","DOIUrl":"https://doi.org/10.1161/CIRCULATIONAHA.124.071498","url":null,"abstract":"","PeriodicalId":10331,"journal":{"name":"Circulation","volume":null,"pages":null},"PeriodicalIF":35.5,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142459509","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":"Early and Late Aortic-Related Mortality and Rupture After Fenestrated-Branched Endovascular Aortic Repair of Thoracoabdominal Aortic Aneurysms: A Prospective Multicenter Cohort Study.","authors":"Gustavo S Oderich, Ying Huang, William S Harmsen, Emanuel R Tenorio, Andres Schanzer, Carlos H Timaran, Darren B Schneider, Bernardo C Mendes, Matthew J Eagleton, Mark A Farber, Warren J Gasper, Adam W Beck, Matthew P Sweet, W Anthony Lee","doi":"10.1161/CIRCULATIONAHA.123.068234","DOIUrl":"10.1161/CIRCULATIONAHA.123.068234","url":null,"abstract":"<p><strong>Background: </strong>Fenestrated-branched endovascular aortic repair (FB-EVAR) has been used as a minimally invasive alternative to open surgical repair to treat patients with thoracoabdominal aortic aneurysms (TAAAs). The aim of this study was to evaluate aortic-related mortality (ARM) and aortic aneurysm rupture after FB-EVAR of TAAAs.</p><p><strong>Methods: </strong>Patients enrolled in 8 prospective, nonrandomized, physician-sponsored investigational device exemption studies between 2005 and 2020 who underwent elective FB-EVAR of asymptomatic intact TAAAs were analyzed. Primary end points were ARM, defined as any early mortality (30 days or in hospital) or late mortality from aortic rupture, dissection, organ or limb malperfusion attributable to aortic disease, complications of reinterventions, or aortic rupture. Secondary end points were early major adverse events, TAAA life-altering events (defined as death, permanent spinal cord injury, permanent dialysis, or stroke), all-cause mortality, and secondary interventions.</p><p><strong>Results: </strong>A total of 1109 patients were analyzed; 589 (53.1%) had extent I-III and 520 (46.9%) had extent IV TAAAs. Median age was 73.4 years (interquartile range, 68.1-78.3 years); 368 (33.2%) were women. Early mortality was 2.7% (n=30); congestive heart failure was associated with early mortality (odds ratio, 3.30 [95% CI, 1.22-8.02]; <i>P</i>=0.01). Incidence of early aortic rupture was 0.4% (n=4). Incidence of early major adverse events and TAAA life-altering events was 20.4% (n=226) and 7.7% (n=85), respectively. There were 30 late ARMs; 5-year cumulative incidence was 3.8% (95% CI, 2.6%-5.4%); older age and extent I-III TAAAs were independently associated with late ARM (each <i>P</i><0.05). Fourteen late aortic ruptures occurred; 5-year cumulative incidence was 2.7% (95% CI, 1.2%-4.3%); extent I-III TAAAs were associated with late aortic rupture (hazard ratio, 5.85 [95% CI, 1.31-26.2]; <i>P</i>=0.02). Five-year all-cause mortality was 45.7% (95% CI, 41.7%-49.4%). Five-year cumulative incidence of secondary intervention was 40.3% (95% CI, 35.8%-44.5%).</p><p><strong>Conclusions: </strong>ARM and aortic rupture are uncommon after elective FB-EVAR of asymptomatic intact TAAAs. Half of the ARMs occurred early, and most of the late deaths were not aortic related. Late all-cause mortality rate and the need for secondary interventions were 46% and 40%, respectively, 5 years after FB-EVAR.</p><p><strong>Registration: </strong>URL: https://www.clinicaltrials.gov; Unique identifiers: NCT02089607, NCT02050113, NCT02266719, NCT02323581, NCT00583817, NCT01654133, NCT00483249, NCT02043691, and NCT01874197.</p>","PeriodicalId":10331,"journal":{"name":"Circulation","volume":null,"pages":null},"PeriodicalIF":35.5,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141579138","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":"Evolution of Coronary Surgery.","authors":"Bruce Lytle","doi":"10.1161/CIRCULATIONAHA.124.070918","DOIUrl":"https://doi.org/10.1161/CIRCULATIONAHA.124.070918","url":null,"abstract":"","PeriodicalId":10331,"journal":{"name":"Circulation","volume":null,"pages":null},"PeriodicalIF":35.5,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142459507","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":"Long-Term Outcomes After Septal Reduction Therapies in Obstructive Hypertrophic Cardiomyopathy: Insights From the SHARE Registry.","authors":"Niccolò Maurizi, Panagiotis Antiochos, Anjali Owens, Neal Lakdwala, Sara Saberi, Mark W Russell, Carlo Fumagalli, Ioannis Skalidis, Kimberly Y Lin, Ashwin S Nathan, Alejandro De Feria Alsina, Nosheen Reza, John C Stendahl, Dominic Abrams, Christopher Semsarian, Brian Clagget, Rachel Lampert, Matthew Wheeler, Victoria N Parikh, Euan Ashley, Michelle Michels, Joseph Rossano, Thomas D Ryan, Jodie Ingles, James Ware, Carolyn Y Ho, Adam S Helms, Sharlene M Day, Iacopo Olivotto","doi":"10.1161/CIRCULATIONAHA.124.069378","DOIUrl":"10.1161/CIRCULATIONAHA.124.069378","url":null,"abstract":"<p><strong>Background: </strong>Septal reduction therapy (SRT) provides substantial symptomatic improvement in patients with obstructive hypertrophic cardiomyopathy (HCM). However, long-term disease course after SRT and predictors of adverse outcomes have not been systematically examined.</p><p><strong>Methods: </strong>Data from 13 high clinical volume HCM centers from the international SHARE (Sarcomeric Human Cardiomyopathy Registry) were analyzed. Patients were followed from the time of SRT until last follow-up or occurrence of heart failure (HF) composite outcome (cardiac transplantation, implantation of a left ventricular assist device, left ventricular ejection fraction <35%, development of New York Heart Association class III or IV symptoms), ventricular arrhythmias composite outcome (sudden cardiac death, resuscitated cardiac arrest, or appropriate implantable cardioverter defibrillator therapy), or HCM-related death. Cox proportional hazards models were used to identify predictors of outcome.</p><p><strong>Results: </strong>Of the 10 225 patients in SHARE, 1832 (18%; 968 [53%] male) underwent SRT, including 455 (25%) with alcohol septal ablation and 1377 (75%) with septal myectomy. The periprocedural 30-day mortality rate was 0.4% (8 of 1832) and 1499 of 1565 (92%) had a maximal left ventricular outflow tract gradient <50 mm Hg at 1 year. After 6.8 years (range, 3.4-9.8 years; 12 565 person-years) from SRT, 77 (4%) experienced HCM-related death (0.6% per year), 236 (13%) a composite HF outcome (1.9% per year), and 87 (5%) a composite ventricular arrhythmia outcome (0.7% per year). Among adults, older age at SRT was associated with a higher incidence of HCM death (hazard ratio, 1.22 [95 CI, 1.1-1.3]; <i>P</i><0.01) and the HF composite (hazard ratio, 1.14 [95 CI, 1.1-1.2] per 5-year increase; <i>P</i><0.01) in a multivariable model. Female patients also had a higher risk of the HF composite after SRT (hazard ratio, 1.4 [95 CI, 1.1-1.8]; <i>P</i><0.01). De novo atrial fibrillation occurred after SRT in 387 patients (21%). Among pediatric patients followed for a median of 13 years after SRT, 26 of 343 (16%) developed the HF composite outcome, despite 96% being free of recurrent left ventricular outflow tract obstruction.</p><p><strong>Conclusions: </strong>Successful short- and long-term relief of outflow tract obstruction was observed in experienced multidisciplinary HCM centers. A subset of patients progressed to develop HF, but event-free survival at 10 years was 83% and ventricular arrhythmias were rare. Older age, female sex, and SRT during childhood were associated with a greater risk of developing HF.</p>","PeriodicalId":10331,"journal":{"name":"Circulation","volume":null,"pages":null},"PeriodicalIF":35.5,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11493522/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142361229","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":"Targeting Sphingosine-1-Phosphate Signaling to Prevent the Progression of Aortic Valve Disease.","authors":"Marcel Benkhoff, Maike Barcik, Philipp Mourikis, Jana Dahlmanns, Paulina Kahmann, Philipp Wollnitzke, Moritz Hering, Tim Huckenbeck, Julia Hoppe, Nina Semleit, Jennifer Deister-Jonas, Saif Zako, Jasmin Seel, Cristina Coman, Mareike Barth, Mareike Cramer, Carolin Helten, Laura Wildeis, Hao Hu, Gabrielle Al-Kassis, Daniel Metzen, Julia Hesse, Jessica Weber, Lisa Dannenberg, Payam Akhyari, Artur Lichtenberg, Christine Quast, Norbert Gerdes, Tobias Zeus, Oliver Borst, Malte Kelm, Tobias Petzold, Robert Ahrends, Bodo Levkau, Amin Polzin","doi":"10.1161/CIRCULATIONAHA.123.067270","DOIUrl":"https://doi.org/10.1161/CIRCULATIONAHA.123.067270","url":null,"abstract":"<p><strong>Background: </strong>Aortic valve disease (AVD) is associated with high mortality and morbidity. To date, there is no pharmacological therapy available to prevent AVD progression. Because valve calcification is the hallmark of AVD and S1P (sphingosine-1-phosphate) plays an important role in osteogenic signaling, we examined the role of S1P signaling in aortic stenosis disease.</p><p><strong>Methods: </strong>AVD progression and its consequences for cardiac function were examined in a murine wire injury-induced AVD model with and without pharmacological and genetic modulation of S1P production, degradation, and receptor signaling. S1P was measured by LC-MS. Calcification of valvular interstitial cells and their response to biomechanical stress were analyzed in the context of S1P signaling. Human explanted aortic valves from patients undergoing aortic valve replacement and cardiovascular magnetic resonance imaging were analyzed for S1P by LC-MS.</p><p><strong>Results: </strong>Raising S1P concentrations in mice with injury-induced AVD by pharmacological inhibition of its sole degrading enzyme S1P lyase vastly enhanced AVD progression and impaired cardiac function resembling human disease. In contrast, low S1P levels caused by SphK1 (sphingosine kinase 1) deficiency potently attenuated AVD progression. We found S1P/S1PR2 (S1P receptor 2) signaling to be responsible for the adverse S1P effect because S1PR2-deficient mice were protected against AVD progression and its deterioration by high S1P. It is important to note that pharmacological S1PR2 inhibition administered after wire injury successfully prevented AVD development. Mechanistically, biomechanical stretch stimulated S1P production by SphK1 in human valvular interstitial cells as measured by C17-S1P generation, whereas S1P/S1PR2 signaling induced their osteoblastic differentiation and calcification through osteogenic RUNX2/OPG signaling and the GSK3β-Wnt-β-catenin pathway. In patients with AVD, stenotic valves exposed to high wall shear stress had higher S1P content and increased SphK1 expression.</p><p><strong>Conclusions: </strong>Increased systemic or local S1P levels lead to increased valvular calcification. S1PR2 antagonists and SphK1 inhibitors may offer feasible pharmacological approaches to human AVD in prophylactic, disease-modifying or relapse-preventing manners.</p>","PeriodicalId":10331,"journal":{"name":"Circulation","volume":null,"pages":null},"PeriodicalIF":35.5,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142459504","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":"Arterial-Lymphatic-Like Endothelial Cells Appear in Hereditary Hemorrhagic Telangiectasia 2 and Contribute to Vascular Leakage and Arteriovenous Malformations.","authors":"Yang Yang, Xiuju Wu, Yan Zhao, Daoqin Zhang, Li Zhang, Xinjiang Cai, Jaden Ji, Zheng Jing, Kristina I Boström, Yucheng Yao","doi":"10.1161/CIRCULATIONAHA.124.070925","DOIUrl":"https://doi.org/10.1161/CIRCULATIONAHA.124.070925","url":null,"abstract":"<p><strong>Background: </strong>Arteriovenous malformations (AVMs) are characteristic of hereditary hemorrhagic telangiectasia. Loss-of-function mutations in the activin receptor-like kinase 1 (<i>Alk1</i>) are linked to hemorrhagic telangiectasia type 2.</p><p><strong>Methods: </strong>Endothelial-specific deletion of <i>Alk1,</i> endothelial lineage tracing, transcriptomics of single-cell analysis, and electron microscopy were performed to examine the vascular phenotype and characteristics of ALK1-deficient endothelial cells (ECs) after EC-specific <i>Alk1</i> deletion. Ischemia assays were used to examine the cell capacity for vascular malformation. Connectivity Map with transcriptomic analysis was applied to identify chemical compounds. Specific methods for arteriovenous malformations, such as micro-computed tomography, with other molecular and cell biological tools were also performed.</p><p><strong>Results: </strong>We performed endothelial-specific deletion of <i>Alk1</i> in mice and found severe arteriovenous malformations and vascular leakage. The transcriptomics of single-cell analysis revealed a new distinctive cell cluster formed after <i>Alk1</i> deletion where the cells coexpressed arterial and lymphatic endothelial markers. The analysis projected that these cells potentially originated from arterial ECs after <i>Alk1</i> deletion. This new population was referred to as arterial-lymphatic-like ECs according to its cellular markers, and its appearance was validated in the pulmonary small arteries after <i>Alk1</i> deletion. Transplantation of these cells caused vascular malformations. Endothelial lineage tracing confirmed that these new arterial-lymphatic-like ECs were derived from ALK1 depleted ECs, potentially arterial ECs. We discovered that SOX17 (SRY-box transcription factor 17) induction was responsible for the derivation of these arterial-lymphatic-like ECs. We showed that direct binding of MDM2 (mouse double minute 2) was required for Sox17 to execute this activity. Inhibition of MDM2 reduced the arteriovenous malformations in the mouse model.</p><p><strong>Conclusions: </strong>Together, our studies revealed the mechanistic underpinnings of ALK1 signaling in regulating the endothelial phenotype and provided possibilities for new therapeutic strategies in hemorrhagic telangiectasia type 2.</p>","PeriodicalId":10331,"journal":{"name":"Circulation","volume":null,"pages":null},"PeriodicalIF":35.5,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142459502","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":"Clinical Correlates and Prognostic Impact of Cognitive Dysfunction in Patients With Heart Failure and Preserved Ejection Fraction: Insights From PARAGON-HF.","authors":"Li Shen, Pooja Dewan, João Pedro Ferreira, Jonathan W Cunningham, Pardeep S Jhund, Inder S Anand, Alvin Chandra, Lu-May Chiang, Brian Claggett, Akshay S Desai, Jianjian Gong, Carolyn S P Lam, Martin P Lefkowitz, Aldo P Maggioni, Felipe Martinez, Milton Packer, Margaret M Redfield, Jean L Rouleau, Dirk J van Veldhuisen, Faiez Zannad, Michael R Zile, Scott D Solomon, John J V McMurray","doi":"10.1161/CIRCULATIONAHA.124.070553","DOIUrl":"https://doi.org/10.1161/CIRCULATIONAHA.124.070553","url":null,"abstract":"<p><strong>Background: </strong>Cognitive impairment is common in patients with heart failure and preserved ejection fraction but its clinical correlates and prognostic associations are poorly understood.</p><p><strong>Methods: </strong>We analyzed cognitive function, using the Mini-Mental State Examination (MMSE), in patients with heart failure and preserved ejection fraction enrolled in a prespecified substudy of the PARAGON-HF trial (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin Receptor Blocker Global Outcomes in Heart Failure With Preserved Ejection Fraction). Logistic regression analyses were performed to determine the variables associated with lower MMSE scores at baseline and postbaseline decline in MMSE scores at 48 weeks. Cox proportional hazards regression and semiparametric proportional rates models were used to examine the risk of clinical outcomes related to baseline MMSE scores, and decline in MMSE scores during follow-up, adjusted for prognostic variables including NT-proBNP (N-terminal pro-B-type natriuretic peptide).</p><p><strong>Results: </strong>At baseline, cognitive function was normal (MMSE score 28-30) in 1809 of 2895 patients (62.5%), borderline (score 24-27) in 794 (27.4%), and impaired (score <24) in 292 (10.1%). Variables associated with both a lower MMSE score at baseline and a decline in score from baseline included older age, a history of stroke or transient ischemia attack, and lower serum albumin. Compared with those with baseline MMSE scores of 28 to 30, patients in the lower MMSE score categories had a stepwise increase in the risk of the composite of time to first HF hospitalization or cardiovascular death, with an adjusted hazard ratio of 1.27 (95% CI, 1.06-1.53) for those with scores of 24 to 27 and 1.58 (95% CI, 1.21-2.06) for those with scores <24, respectively. These associations were also found for the individual components of the composite and all-cause death. Likewise, cognitive impairment was associated with a 50% higher risk of total (first and repeat) heart failure hospitalizations and cardiovascular deaths. Examining the change in MMSE score from baseline, a decrease in MMSE score during follow-up was associated with a higher risk of death.</p><p><strong>Conclusions: </strong>In patients with heart failure and preserved ejection fraction, even modest baseline impairment of cognitive function was associated with worse outcomes, including death. A decline in MMSE score during follow-up was a strong predictor of mortality, independent of other prognostic variables.</p>","PeriodicalId":10331,"journal":{"name":"Circulation","volume":null,"pages":null},"PeriodicalIF":35.5,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142459503","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":"Arterial-Lymphatic-Like Endothelial Cells Appear in Hereditary Hemorrhagic Telangiectasia 2 and Contribute to Vascular Leakage and Arteriovenous Malformations.","authors":"Yang Yang,Xiuju Wu,Yan Zhao,Daoqin Zhang,Li Zhang,Xinjiang Cai,Jaden Ji,Zheng Jing,Kristina I Boström,Yucheng Yao","doi":"10.1161/circulationaha.124.070925","DOIUrl":"https://doi.org/10.1161/circulationaha.124.070925","url":null,"abstract":"BACKGROUNDArteriovenous malformations (AVMs) are characteristic of hereditary hemorrhagic telangiectasia. Loss-of-function mutations in the activin receptor-like kinase 1 (Alk1) are linked to hemorrhagic telangiectasia type 2.METHODSEndothelial-specific deletion of Alk1, endothelial lineage tracing, transcriptomics of single-cell analysis, and electron microscopy were performed to examine the vascular phenotype and characteristics of ALK1-deficient endothelial cells (ECs) after EC-specific Alk1 deletion. Ischemia assays were used to examine the cell capacity for vascular malformation. Connectivity Map with transcriptomic analysis was applied to identify chemical compounds. Specific methods for arteriovenous malformations, such as micro-computed tomography, with other molecular and cell biological tools were also performed.RESULTSWe performed endothelial-specific deletion of Alk1 in mice and found severe arteriovenous malformations and vascular leakage. The transcriptomics of single-cell analysis revealed a new distinctive cell cluster formed after Alk1 deletion where the cells coexpressed arterial and lymphatic endothelial markers. The analysis projected that these cells potentially originated from arterial ECs after Alk1 deletion. This new population was referred to as arterial-lymphatic-like ECs according to its cellular markers, and its appearance was validated in the pulmonary small arteries after Alk1 deletion. Transplantation of these cells caused vascular malformations. Endothelial lineage tracing confirmed that these new arterial-lymphatic-like ECs were derived from ALK1 depleted ECs, potentially arterial ECs. We discovered that SOX17 (SRY-box transcription factor 17) induction was responsible for the derivation of these arterial-lymphatic-like ECs. We showed that direct binding of MDM2 (mouse double minute 2) was required for Sox17 to execute this activity. Inhibition of MDM2 reduced the arteriovenous malformations in the mouse model.CONCLUSIONSTogether, our studies revealed the mechanistic underpinnings of ALK1 signaling in regulating the endothelial phenotype and provided possibilities for new therapeutic strategies in hemorrhagic telangiectasia type 2.","PeriodicalId":10331,"journal":{"name":"Circulation","volume":null,"pages":null},"PeriodicalIF":37.8,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142486327","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 Sphingosine-1-Phosphate Signaling to Prevent the Progression of Aortic Valve Disease.","authors":"Marcel Benkhoff,Maike Barcik,Philipp Mourikis,Jana Dahlmanns,Paulina Kahmann,Philipp Wollnitzke,Moritz Hering,Tim Huckenbeck,Julia Hoppe,Nina Semleit,Jennifer Deister-Jonas,Saif Zako,Jasmin Seel,Cristina Coman,Mareike Barth,Mareike Cramer,Carolin Helten,Laura Wildeis,Hao Hu,Gabrielle Al-Kassis,Daniel Metzen,Julia Hesse,Jessica Weber,Lisa Dannenberg,Payam Akhyari,Artur Lichtenberg,Christine Quast,Norbert Gerdes,Tobias Zeus,Oliver Borst,Malte Kelm,Tobias Petzold,Robert Ahrends,Bodo Levkau,Amin Polzin","doi":"10.1161/circulationaha.123.067270","DOIUrl":"https://doi.org/10.1161/circulationaha.123.067270","url":null,"abstract":"BACKGROUNDAortic valve disease (AVD) is associated with high mortality and morbidity. To date, there is no pharmacological therapy available to prevent AVD progression. Because valve calcification is the hallmark of AVD and S1P (sphingosine-1-phosphate) plays an important role in osteogenic signaling, we examined the role of S1P signaling in aortic stenosis disease.METHODSAVD progression and its consequences for cardiac function were examined in a murine wire injury-induced AVD model with and without pharmacological and genetic modulation of S1P production, degradation, and receptor signaling. S1P was measured by LC-MS. Calcification of valvular interstitial cells and their response to biomechanical stress were analyzed in the context of S1P signaling. Human explanted aortic valves from patients undergoing aortic valve replacement and cardiovascular magnetic resonance imaging were analyzed for S1P by LC-MS.RESULTSRaising S1P concentrations in mice with injury-induced AVD by pharmacological inhibition of its sole degrading enzyme S1P lyase vastly enhanced AVD progression and impaired cardiac function resembling human disease. In contrast, low S1P levels caused by SphK1 (sphingosine kinase 1) deficiency potently attenuated AVD progression. We found S1P/S1PR2 (S1P receptor 2) signaling to be responsible for the adverse S1P effect because S1PR2-deficient mice were protected against AVD progression and its deterioration by high S1P. It is important to note that pharmacological S1PR2 inhibition administered after wire injury successfully prevented AVD development. Mechanistically, biomechanical stretch stimulated S1P production by SphK1 in human valvular interstitial cells as measured by C17-S1P generation, whereas S1P/S1PR2 signaling induced their osteoblastic differentiation and calcification through osteogenic RUNX2/OPG signaling and the GSK3β-Wnt-β-catenin pathway. In patients with AVD, stenotic valves exposed to high wall shear stress had higher S1P content and increased SphK1 expression.CONCLUSIONSIncreased systemic or local S1P levels lead to increased valvular calcification. S1PR2 antagonists and SphK1 inhibitors may offer feasible pharmacological approaches to human AVD in prophylactic, disease-modifying or relapse-preventing manners.","PeriodicalId":10331,"journal":{"name":"Circulation","volume":null,"pages":null},"PeriodicalIF":37.8,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142486330","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":"Clinical Correlates and Prognostic Impact of Cognitive Dysfunction in Patients With Heart Failure and Preserved Ejection Fraction: Insights From PARAGON-HF.","authors":"Li Shen,Pooja Dewan,João Pedro Ferreira,Jonathan W Cunningham,Pardeep S Jhund,Inder S Anand,Alvin Chandra,Lu-May Chiang,Brian Claggett,Akshay S Desai,Jianjian Gong,Carolyn S P Lam,Martin P Lefkowitz,Aldo P Maggioni,Felipe Martinez,Milton Packer,Margaret M Redfield,Jean L Rouleau,Dirk J van Veldhuisen,Faiez Zannad,Michael R Zile,Scott D Solomon,John J V McMurray","doi":"10.1161/circulationaha.124.070553","DOIUrl":"https://doi.org/10.1161/circulationaha.124.070553","url":null,"abstract":"BACKGROUNDCognitive impairment is common in patients with heart failure and preserved ejection fraction but its clinical correlates and prognostic associations are poorly understood.METHODSWe analyzed cognitive function, using the Mini-Mental State Examination (MMSE), in patients with heart failure and preserved ejection fraction enrolled in a prespecified substudy of the PARAGON-HF trial (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin Receptor Blocker Global Outcomes in Heart Failure With Preserved Ejection Fraction). Logistic regression analyses were performed to determine the variables associated with lower MMSE scores at baseline and postbaseline decline in MMSE scores at 48 weeks. Cox proportional hazards regression and semiparametric proportional rates models were used to examine the risk of clinical outcomes related to baseline MMSE scores, and decline in MMSE scores during follow-up, adjusted for prognostic variables including NT-proBNP (N-terminal pro-B-type natriuretic peptide).RESULTSAt baseline, cognitive function was normal (MMSE score 28-30) in 1809 of 2895 patients (62.5%), borderline (score 24-27) in 794 (27.4%), and impaired (score <24) in 292 (10.1%). Variables associated with both a lower MMSE score at baseline and a decline in score from baseline included older age, a history of stroke or transient ischemia attack, and lower serum albumin. Compared with those with baseline MMSE scores of 28 to 30, patients in the lower MMSE score categories had a stepwise increase in the risk of the composite of time to first HF hospitalization or cardiovascular death, with an adjusted hazard ratio of 1.27 (95% CI, 1.06-1.53) for those with scores of 24 to 27 and 1.58 (95% CI, 1.21-2.06) for those with scores <24, respectively. These associations were also found for the individual components of the composite and all-cause death. Likewise, cognitive impairment was associated with a 50% higher risk of total (first and repeat) heart failure hospitalizations and cardiovascular deaths. Examining the change in MMSE score from baseline, a decrease in MMSE score during follow-up was associated with a higher risk of death.CONCLUSIONSIn patients with heart failure and preserved ejection fraction, even modest baseline impairment of cognitive function was associated with worse outcomes, including death. A decline in MMSE score during follow-up was a strong predictor of mortality, independent of other prognostic variables.","PeriodicalId":10331,"journal":{"name":"Circulation","volume":null,"pages":null},"PeriodicalIF":37.8,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142486338","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}