Circulation最新文献

{"title":"Direct-to-Consumer Genetic Testing for Cardiovascular Disease: A Scientific Statement From the American Heart Association.","authors":"Leland E Hull, Aaron W Aday, Quan M Bui, Jasmine A Luzum, James M Muchira, Hannah Wand, C Anwar A Chahal, Mina K Chung, Anne E Kwitek, Silvana Molossi, Pradeep Natarajan","doi":"10.1161/CIR.0000000000001304","DOIUrl":"https://doi.org/10.1161/CIR.0000000000001304","url":null,"abstract":"<p><p>Despite insufficient evidence to support direct-to-consumer genetic testing in routine clinical care, cardiovascular clinicians increasingly face questions about its utility and interpretation because individuals can purchase these tests directly from laboratories. A burgeoning marketplace offers an expanding array of testing options. In many cases, direct-to-consumer genetic testing advertises information that could inform one's risk of heritable disease, including insight into having a genetic predisposition to cardiovascular disease or data about gene-drug interactions that could affect response to cardiovascular medications. Navigating clinical questions about direct-to-consumer genetic testing involves understanding the evolution and oversight of the marketplace; the scope of direct-to-consumer genetic testing offerings; and the risks, benefits, and limitations of said testing. In this American Heart Association scientific statement, we summarize the state of the direct-to-consumer genetic testing industry, review types of cardiovascular genetic information that may be included in direct-to-consumer genetic testing, describe approaches to evaluate test quality, and provide resources for clinicians navigating questions about direct-to-consumer genetic testing. If direct-to-consumer genetic test information is used in clinical care, care should be taken to assess the limitations of the test, to contextualize the information specifically to the patient, and to corroborate potentially actionable monogenic findings.</p>","PeriodicalId":10331,"journal":{"name":"Circulation","volume":" ","pages":""},"PeriodicalIF":35.5,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143613761","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":"An NRF2/β3-Adrenoreceptor Axis Drives a Sustained Antioxidant and Metabolic Rewiring Through the Pentose-Phosphate Pathway to Alleviate Cardiac Stress.","authors":"Lauriane Y M Michel, Hrag Esfahani, Delphine De Mulder, Roxane Verdoy, Jérôme Ambroise, Véronique Roelants, Bertrand Bouchard, Nathalie Fabian, Jérôme Savary, Joseph P Dewulf, Thomas Doumont, Caroline Bouzin, Vincent Haufroid, Joost J F P Luiken, Miranda Nabben, Michael L Singleton, Luc Bertrand, Matthieu Ruiz, Christine Des Rosiers, Jean-Luc Balligand","doi":"10.1161/CIRCULATIONAHA.124.067876","DOIUrl":"https://doi.org/10.1161/CIRCULATIONAHA.124.067876","url":null,"abstract":"<p><strong>Background: </strong>Cardiac β3-adrenergic receptors (ARs) are upregulated in diseased hearts and mediate antithetic effects to those of β1AR and β2AR. β3AR agonists were recently shown to protect against myocardial remodeling in preclinical studies and to improve systolic function in patients with severe heart failure. However, the underlying mechanisms remain elusive.</p><p><strong>Methods: </strong>To dissect functional, transcriptional, and metabolic effects, hearts and isolated ventricular myocytes from mice harboring a moderate, cardiac-specific expression of a human <i>ADRB3</i> transgene (β3AR-Tg) and subjected to transverse aortic constriction were assessed with echocardiography, RNA sequencing, positron emission tomography scan, metabolomics, and metabolic flux analysis. Subsequently, signaling and metabolic pathways were further investigated in vivo in β3AR-Tg and ex vivo in neonatal rat ventricular myocytes adenovirally infected to express β3AR and subjected to neurohormonal stress. These results were complemented with an analysis of single-nucleus RNA-sequencing data from human cardiac myocytes from patients with heart failure.</p><p><strong>Results: </strong>Compared with wild-type littermates, β3AR-Tg mice were protected from hypertrophy after transaortic constriction, and systolic function was preserved. β3AR-expressing hearts displayed enhanced myocardial glucose uptake under stress in the absence of increased lactate levels. Instead, metabolomic and metabolic flux analyses in stressed hearts revealed an increase in intermediates of the pentose-phosphate pathway in β3AR-Tg, an alternative route of glucose utilization, paralleled with increased transcript levels of NADPH-producing and rate-limiting enzymes of the pentose-phosphate pathway, without fueling the hexosamine metabolism. The ensuing increased content of NADPH and of reduced glutathione decreased myocyte oxidant stress, whereas downstream oxidative metabolism assessed by oxygen consumption was preserved with higher glucose oxidation in β3AR-Tg mice after transaortic constriction compared with wild type, together with increased mitochondrial biogenesis. Unbiased transcriptomics and pathway analysis identified NRF2 (NFE2L2) as an upstream transcription factor that was functionally verified in vivo and in β3AR-expressing cardiac myocytes, where its translocation and nuclear activity were dependent on β3AR activation of nitric oxide synthase and nitric oxide production through S-nitrosation of the NRF2-negative regulator Keap1.</p><p><strong>Conclusions: </strong>Moderate expression of cardiac β3AR, at levels observed in human cardiac myocardium, exerts metabolic and antioxidant effects through activation of the pentose-phosphate pathway and NRF2 pathway through S-nitrosation of Keap1, thereby preserving myocardial oxidative metabolism, function, and integrity under pathophysiological stress.</p>","PeriodicalId":10331,"journal":{"name":"Circulation","volume":" ","pages":""},"PeriodicalIF":35.5,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143604079","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":"PCSK9 Promotes LDLR Degradation by Preventing SNX17-Mediated LDLR Recycling.","authors":"YangYang Guan, Xiaomin Liu, Zetian Yang, Xinyu Zhu, Min Liu, Mingkun Du, Xiaowei Pan, Yan Wang","doi":"10.1161/CIRCULATIONAHA.124.072336","DOIUrl":"https://doi.org/10.1161/CIRCULATIONAHA.124.072336","url":null,"abstract":"<p><strong>Background: </strong>Low-density lipoprotein (LDL) is internalized into cells mainly through LDLR (LDL receptor)-mediated endocytosis. In an acidic endosome, LDLR is released from LDL and recycles back to the cell surface, whereas LDL is left in the endosome and degraded in the lysosome. Circulating PCSK9 (proprotein convertase subtilisin/kexin 9) binds with LDLR and is internalized into the endosome, similar to LDL. In an acidic endosome, LDLR fails to disassociate from PCSK9, and both proteins are degraded in the lysosome. PCSK9 inhibitors are widely used for treating hypercholesterolemia. However, how PCSK9 diverts LDLR to the lysosome for degradation remains elusive. Some patients are resistant to PCSK9 inhibitors, for unknown reasons.</p><p><strong>Methods: </strong>Both in vitro and in vivo approaches were used to investigate the molecular and cellular mechanisms of PCSK9-mediated LDLR degradation. LDLR containing <i>FH</i> sequence variations was expressed in <i>LDLR</i> knockout mice and knockout HuH7 cells to evaluate their response to PCSK9 and PCSK9 inhibitors.</p><p><strong>Results: </strong>Acidic pH induces a conformational change in LDLR extracellular domain and promotes its interaction with SNX17 (sorting nexin 17) through the intracellular domain. Knocking down <i>SNX17</i> abolishes LDLR recycling and causes accelerated degradation in the lysosome. PCSK9 prevents the acidic pH-induced conformational change in LDLR and blocks its interaction with SNX17. Knocking down <i>SNX17</i> abolishes PCSK9-mediated LDLR degradation. Any <i>FH</i> sequence variations that disrupt LDLR recycling are unresponsive to PCSK9 or PCSK9 inhibitors, even though they can internalize LDL.</p><p><strong>Conclusions: </strong>PCSK9 promotes LDLR degradation by preventing SNX17-mediated LDLR recycling. Patients with sequence variations in <i>FH</i> leading to defects in LDLR recycling are resistant to PCSK9 inhibitors. Genetic diagnosis and alternative drugs independent of LDLR will be needed for treatment of these patients.</p>","PeriodicalId":10331,"journal":{"name":"Circulation","volume":" ","pages":""},"PeriodicalIF":35.5,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143604095","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":"Myeloid Fatty Acid Metabolism Activates Neighboring Hematopoietic Stem Cells to Promote Heart Failure With Preserved Ejection Fraction.","authors":"Mallory Filipp, Zhi-Dong Ge, Matthew DeBerge, Connor Lantz, Kristofor Glinton, Peng Gao, Sasha Smolgovsky, Jingbo Dai, You-Yang Zhao, Laurent Yvan-Charvet, Pilar Alcaide, Samuel E Weinberg, Gabriele G Schiattarella, Joseph A Hill, Matthew J Feinstein, Sanjiv J Shah, Edward B Thorp","doi":"10.1161/CIRCULATIONAHA.124.070248","DOIUrl":"10.1161/CIRCULATIONAHA.124.070248","url":null,"abstract":"<p><strong>Background: </strong>Despite the high morbidity and mortality of heart failure with preserved ejection fraction (HFpEF), treatment options remain limited. The HFpEF syndrome is associated with a high comorbidity burden, including high prevalence of obesity and hypertension. Although inflammation is implicated to play a key role in HFpEF pathophysiology, underlying causal mechanisms remain unclear.</p><p><strong>Methods: </strong>Comparing patient samples and animal models, we defined the innate immune response during HFpEF in situ and through flow cytometry and single-cell RNA sequencing. After identifying transcriptional and cell signatures, we implemented a high-fat diet and hypertensive model of HFpEF and tested roles for myeloid and hematopoietic stem cells during HFpEF. Contributions of macrophage metabolism were also evaluated, including through mass spectrometry and carbon labeling. Primary macrophages were studied ex vivo to gain insight into complementary cell-intrinsic mechanisms.</p><p><strong>Results: </strong>Here we report evidence that patients with cardiometabolic HFpEF exhibit elevated peripheral blood hematopoietic stem cells. This phenotype was conserved across species in a murine mode of high-fat diet and hypertension. Hematopoietic stem cell proliferation was coupled to striking remodeling of the peripheral hematopoietic stem cell niche and expression of the macrophage adhesion molecule <i>Vcam1</i>. This could be partially inhibited by sodium-glucose cotransporter-2 inhibitors and explained by elevated fatty acid metabolism in macrophage mitochondria, which in turn remodeled the <i>Vcam1</i> promoter to enhance its expression.</p><p><strong>Conclusions: </strong>These findings identify a significant new stem cell signature of cardiometabolic HFpEF and support a role for myeloid maladaptive fatty acid metabolism in the promotion of systemic inflammation and cardiac diastolic dysfunction.</p>","PeriodicalId":10331,"journal":{"name":"Circulation","volume":" ","pages":""},"PeriodicalIF":35.5,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143604091","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":"Temporal Effects of Plozasiran on Lipids and Lipoproteins in Persistent Chylomicronemia.","authors":"Gerald F Watts, Robert A Hegele, Robert S Rosenson, Ira J Goldberg, Antonio Gallo, Ann Mertens, Alexis Baass, Rong Zhou, Ma'an Muhsin, Jennifer Hellawell, Daniel Gaudet, Nicholas J Leeper","doi":"10.1161/CIRCULATIONAHA.124.072860","DOIUrl":"10.1161/CIRCULATIONAHA.124.072860","url":null,"abstract":"","PeriodicalId":10331,"journal":{"name":"Circulation","volume":" ","pages":"733-736"},"PeriodicalIF":35.5,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142643881","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":"Neutrophil CRACR2A Promotes Neutrophil Recruitment in Sterile Inflammation and Ischemic Stroke.","authors":"Jingu Lee, Brett Balzraine, Alexis Schweizer, Vasilisa Kuzmanova, Yousang Gwack, Babak Razani, Jin-Moo Lee, Deane F Mosher, Jaehyung Cho","doi":"10.1161/CIRCULATIONAHA.124.070487","DOIUrl":"10.1161/CIRCULATIONAHA.124.070487","url":null,"abstract":"<p><strong>Background: </strong>Ca²⁺ release-activated Ca²⁺ channel regulator 2A (CRACR2A) has been linked to immunodeficiency attributable to T-cell dysfunction in humans. We discovered that neutrophil CRACR2A promotes neutrophil adhesive and migratory functions by facilitating Ca²⁺ mobilization and β2 integrin activation.</p><p><strong>Methods: </strong>Myeloid-specific Cracr2a conditional knockout mice and intravital microscopy were used to investigate the physiologic role of neutrophil Cracr2a in neutrophil recruitment in vascular inflammation. Cracr2a-deficient neutrophils or dHL-60 (differentiated human promyelocytic leukemia) cells and Cracr2a-derived peptides were used in flow cytometry, immunoprecipitation, cytosolic Ca²⁺ mobilization, and flow chamber assays to elucidate the molecular mechanism. Four-dimensional confocal intravital microscopy of mice after focal brain ischemia and single neutrophil behavioral analysis demonstrated the pathologic role of neutrophil Cracr2a in brain damage.</p><p><strong>Results: </strong>Compared with wild-type control mice, Cracr2a conditional knockout mice exhibited significantly reduced adhesion, crawling, and transmigration of neutrophils on ear and cremaster venules in tumor necrosis factor-α-induced sterile inflammation. Neutrophil Cracr2a rapidly interacts with Stim1 (stromal interaction molecule 1) after agonist stimulation and facilitates Ca²⁺ mobilization, increasing the ligand-binding function of β2 integrin. Our findings in Cracr2a-deficient mouse neutrophils are recapitulated in dHL-60 cells, in which CRACR2A is deleted by CRISPR/Cas9. Furthermore, overexpression of CRACR2A in CRACR2A KO dHL-60 cells restores normal function. Using a series of peptides covering the coiled-coil region of Cracr2a, we identified a palmitoylated 20-mer that blocks Stim1-Cracr2a interaction. Treating neutrophils with this 20-mer inhibits Ca²⁺ mobilization and β2 integrin activation after agonist stimulation, reducing neutrophil recruitment to an activated endothelial cell monolayer under venous shear stress and to ear venules in tumor necrosis factor-α-challenged mice. Cerebral 4-dimensional intravital microscopy of mice after focal brain ischemia revealed that neutrophil Cracr2a enhances the emergence of highly migratory neutrophils by increasing the surface level of αMβ2 integrin, thereby facilitating neutrophil infiltration into brain tissue and exacerbating brain injury.</p><p><strong>Conclusions: </strong>Our results demonstrate that neutrophil CRACR2A promotes neutrophil recruitment to sites of sterile inflammation, such as ischemic stroke. Blocking the STIM1-CRACR2A interaction may be a novel therapeutic strategy to mitigate inflammation and consequent tissue injury.</p>","PeriodicalId":10331,"journal":{"name":"Circulation","volume":" ","pages":"696-715"},"PeriodicalIF":35.5,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11893261/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142726533","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":"Prevalence and Clinical Outcomes of Discordant Lesions Between Fractional Flow Reserve and Nonhyperemic Pressure Ratios in Clinical Practice: The J-PRIDE Registry.","authors":"Shoichi Kuramitsu, Yoshiaki Kawase, Tomohiro Shinozaki, Takenori Domei, Futoshi Yamanaka, Umihiko Kaneko, Tsunekazu Kakuta, Kazunori Horie, Hidenobu Terai, Hirohiko Ando, Yasutsugu Shiono, Toru Tagashira, Kazutaka Nogi, Takashi Kubo, Taku Asano, Jun Shiraishi, Hiromasa Otake, Akinori Sugano, Reo Anai, Atsushi Iwai, Yuetsu Kikuta, Hidetaka Nishina, Tsutomu Fujita, Tetsuya Amano, Masashi Iwabuchi, Hiroyoshi Yokoi, Takashi Akasaka, Hitoshi Matsuo, Nobuhiro Tanaka","doi":"10.1161/CIRCULATIONAHA.124.071139","DOIUrl":"10.1161/CIRCULATIONAHA.124.071139","url":null,"abstract":"<p><strong>Background: </strong>Limited large-scale, real-world data exist on the prevalence and clinical impact of discordance between fractional flow reserve (FFR) and nonhyperemic pressure ratios (NHPRs).</p><p><strong>Methods: </strong>The J-PRIDE registry (Clinical Outcomes of Japanese Patients With Coronary Artery Disease Assessed by Resting Indices and Fractional Flow Reserve: A Prospective Multicenter Registry) prospectively enrolled 4304 lesions in 3200 patients from 20 Japanese centers. The lesions were classified into FFR+/NHPR-, FFR-/NHPR+, FFR+/NHPR+, or FFR-/NHPR groups according to cutoff values of 0.89 for NHPRs and 0.80 for FFR. The primary study end point was the cumulative 1-year incidence of target vessel failure (a composite of cardiac death, target vessel-related myocardial infarction, and clinically driven target vessel revascularization) on a lesion basis.</p><p><strong>Results: </strong>An NHPR cutoff value of 0.89, determined using online software, predicted an FFR of 0.80 across various NHPR types. Discordance between FFR and NHPRs was observed in 20% of lesions (FFR+/NHPR-, 11.2%; FFR-/NHPRs+, 8.8%). Revascularization was deferred in 42.9% and 88.4% of the FFR+/NHPR- and FFR-/NHPR+ groups, respectively. In deferred vessels, the FFR+/NHPR- and FFR-/NHPR+ groups showed a higher 1-year incidence of target vessel failure compared with the FFR-/NHPR- group (7.9% versus 5.5% versus 1.7%; for FFR+/NHPR-, adjusted hazard ratio [aHR], 4.89 [95% CI, 2.68-8.91]; <i>P</i><0.001; for FFR-/NHPR+, aHR, 2.64 [95% CI, 1.49-4.69]; <i>P</i><0.001). In revascularized vessels, the 1-year target vessel failure rate was numerically higher in the FFR-/NHPR+ group than in the FFR+/NHPR+ group (9.6% versus 3.4%; aHR, 2.27 [95% CI, 0.70-7.34]; <i>P</i>=0.17), although with similar outcomes between the FFR+/NHPR- and FFR+/NHPR+ groups (2.3% versus 3.4%; aHR, 0.96 [95% CI, 0.37-2.38]; <i>P</i>=0.93). The FFR+/NHPR- group benefited from revascularization compared with medical treatment (aHR, 0.26 [95% CI, 0.08-0.86]; <i>P</i>=0.027); the FFR-/NHPR+ group did not (aHR, 2.39 [95% CI, 0.62-9.21]; <i>P</i>=0.20).</p><p><strong>Conclusions: </strong>Discordance between FFR and NHPRs was noted in 20% of lesions, and discordant deferred lesions resulted in worse outcomes than concordant negative lesions. Although the outcomes after deferring revascularization were comparable between the FFR+/NHPR- and FFR-/NHPR+ lesions, only FFR+/NHPR- lesions showed a benefit from revascularization compared with medical treatment, suggesting that an FFR-guided strategy is superior to an NHPR-guided strategy in discordant lesions.</p><p><strong>Registration: </strong>URL: https://www.umin.ac.jp; Unique identifier: UMIN000038403.</p>","PeriodicalId":10331,"journal":{"name":"Circulation","volume":" ","pages":"672-685"},"PeriodicalIF":35.5,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142945760","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":"Effects of Tirzepatide on the Clinical Trajectory of Patients With Heart Failure, Preserved Ejection Fraction, and Obesity.","authors":"Michael R Zile, Barry A Borlaug, Christopher M Kramer, Seth J Baum, Sheldon E Litwin, Venu Menon, Yang Ou, Govinda J Weerakkody, Karla C Hurt, Chisom Kanu, Masahiro Murakami, Milton Packer","doi":"10.1161/CIRCULATIONAHA.124.072679","DOIUrl":"10.1161/CIRCULATIONAHA.124.072679","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Patients with heart failure with preserved ejection fraction and obesity have significant disability and frequent exacerbations of heart failure. We hypothesized that tirzepatide, a long-acting agonist of glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors, would improve a comprehensive suite of clinical end points, including measures of health status, functional capacity, quality of life, exercise tolerance, patient well-being, and medication burden, in these patients.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;We randomized (double-blind) 731 patients with class II to IV heart failure, ejection fraction ≥50%, and body mass index ≥30 kg/m&lt;sup&gt;2&lt;/sup&gt; to tirzepatide (titrated up to 15 mg SC weekly; n=364) or placebo (n=367) added to background therapy for a median of 104 weeks (quartile 1, 66; quartile 3, 126 weeks). The primary end points were whether tirzepatide reduced the combined risk of cardiovascular death or worsening heart failure and improved Kansas City Cardiomyopathy Questionnaire Clinical Summary Score. The current expanded analysis included sensitivity analyses of the primary end points, 6-minute walk distance, EQ-5D-5L health state index, Patient Global Impression of Severity Overall Health score, New York Heart Association class, use of heart failure medications, and a hierarchical composite based on all-cause death, worsening heart failure, and 52-week changes in Kansas City Cardiomyopathy Questionnaire Clinical Summary Score and 6-minute walk distance.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Patients were 65.2±10.7 years of age; 53.8% (n=393) were female; body mass index was 38.2±6.7 kg/m&lt;sup&gt;2&lt;/sup&gt;; Kansas City Cardiomyopathy Questionnaire Clinical Summary Score was 53.5±18.5; 6-minute walk distance was 302.8±81.7 m; and 53% (n=388) had a worsening heart failure event in the previous 12 months. Compared with placebo, tirzepatide produced a consistent beneficial effect across all composites of death and worsening heart failure events, analyzed as time to first event (hazard ratios, 0.41-0.67). At 52 weeks, tirzepatide increased the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score by 6.9 points (95% CI, 3.3-10.6; &lt;i&gt;P&lt;/i&gt;&lt;0.001), 6-minute walk distance 18.3 meters (95% CI, 9.9-26.7; &lt;i&gt;P&lt;/i&gt;&lt;0.001), and EQ-5D-5L 0.06 (95% CI, 0.03-0.09; &lt;i&gt;P&lt;/i&gt;&lt;0.001). The tirzepatide group shifted to a more favorable Patient Global Impression of Severity Overall Health score (proportional odds ratio, 1.99 [95% CI, 1.44-2.76]) and New York Heart Association class (proportional odds ratio, 2.26 [95% CI, 1.54-3.31]; both &lt;i&gt;P&lt;/i&gt;&lt;0.001) and required fewer heart failure medications (&lt;i&gt;P&lt;/i&gt;=0.015). The broad spectrum of effects was reflected in benefits on the hierarchical composite (win ratio, 1.63 [95% CI, 1.17-2.28]; &lt;i&gt;P&lt;/i&gt;=0.004).&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;Tirzepatide produced a comprehensive, meaningful improvement in heart failure across multiple complementary domains; e","PeriodicalId":10331,"journal":{"name":"Circulation","volume":" ","pages":"656-668"},"PeriodicalIF":35.5,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11893002/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142667428","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":"Albuminuria in Cardiovascular, Kidney, and Metabolic Disorders: A State-of-the-Art Review.","authors":"Sophie E Claudel, Ashish Verma","doi":"10.1161/CIRCULATIONAHA.124.071079","DOIUrl":"10.1161/CIRCULATIONAHA.124.071079","url":null,"abstract":"<p><p>Albuminuria-increased urine albumin excretion-is associated with cardiovascular mortality among patients with diabetes, hypertension, chronic kidney disease, or heart failure, as well as among adults with few cardiovascular risk factors. Many authors have hypothesized that albuminuria reflects widespread endothelial dysfunction, but additional work is needed to uncover whether albuminuria is directly pathologic or causative of cardiovascular disease. Urinary albumin-to-creatinine ratio is an attractive, unifying biomarker of cardiovascular, kidney, and metabolic conditions that may be useful for identifying and monitoring disease trajectory. However, albuminuria may develop through unique mechanisms across these distinct clinical phenotypes. This state-of-the-art review discusses the role of albuminuria in cardiovascular, kidney, and metabolic conditions; identifies potential pathways linking albuminuria to adverse outcomes; and provides practical approaches to screening and managing albuminuria for clinical cardiologists. Future research is needed to determine how broadly and how frequently to screen patients for albuminuria, whether it is cost-effective to treat low-grade albuminuria (10-30 mg/g), and how to equitably offer newer antiproteinuric therapies across the spectrum of cardiovascular-kidney-metabolic diseases.</p>","PeriodicalId":10331,"journal":{"name":"Circulation","volume":"151 10","pages":"716-732"},"PeriodicalIF":35.5,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11902889/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143596373","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":"Holistic View of Tirzepatide's Role in Obesity-Related HFpEF.","authors":"Neha J Pagidipati","doi":"10.1161/CIRCULATIONAHA.125.073439","DOIUrl":"https://doi.org/10.1161/CIRCULATIONAHA.125.073439","url":null,"abstract":"","PeriodicalId":10331,"journal":{"name":"Circulation","volume":"151 10","pages":"669-671"},"PeriodicalIF":35.5,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143596463","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}