Circulation最新文献

{"title":"Determining the Physiological Threshold for Angina (ORBITA-FIRE): A Double-Blind, Randomized, Placebo-Controlled Study.","authors":"Fiyyaz Ahmed-Jushuf, Michael J Foley, Shayna Chotai, Christopher A Rajkumar, Danqi Wang, Florentina A Simader, Krzysztof Macierzanka, Kayla Chiew, Sannidhya Misra, Rupert Williams, Klio Konstantinou, Jehangir N Din, Shah R Mohdnazri, Peter D O'Kane, Peter Haworth, Sukhjinder S Nijjer, Henry Seligman, Thomas R Keeble, John R Davies, Gerald Clesham, Jonathan Hinton, James C Spratt, Jason N Dungu, Daniel Knight, Tushar Kotecha, Frank E Harrell, James P Howard, Darrel P Francis, Matthew J Shun-Shin, Rasha K Al-Lamee","doi":"10.1161/CIRCULATIONAHA.125.078738","DOIUrl":"https://doi.org/10.1161/CIRCULATIONAHA.125.078738","url":null,"abstract":"<p><strong>Background: </strong>In stable coronary artery disease, the primary goal of percutaneous coronary intervention (PCI) is symptom relief. Fractional flow reserve (FFR) and nonhyperemic pressure ratios such as resting full-cycle ratio (RFR) are used to guide revascularization. Although these indices correlate with myocardial ischemia, they have never been validated against the onset of angina. The physiological thresholds for angina (FFR_angina and RFR_angina) at rest and during exercise remain undefined.</p><p><strong>Methods: </strong>ORBITA-FIRE (Finding the Invasive Threshold for Symptom Relief in Exertional Angina) was a multicenter, double-blind, randomized, placebo-controlled study in patients with stable angina and single-vessel coronary artery disease. After imaging-guided PCI, an in-stent balloon was incrementally inflated until angina occurred at rest. This angina threshold was verified against placebo inflation, and corresponding FFR_angina and RFR_angina values were recorded at symptom onset. The protocol was repeated during low- and high-intensity exercise to assess changes in angina thresholds with increasing cardiac workload.</p><p><strong>Results: </strong>Sixty-five patients were enrolled (mean age, 63.9±8.7 years; 74% male; 69% hypertensive; 23% diabetic; 91% with Canadian Cardiovascular Society class II-III angina). Median pre-PCI FFR was 0.59 (interquartile range [IQR], 0.46-0.70) and RFR was 0.61 (IQR, 0.40-0.82). Median FFR_angina at rest was 0.29 (IQR, 0.23-0.35), increasing to 0.38 (IQR, 0.30-0.48) during low-intensity exercise and 0.45 (IQR, 0.36-0.55) during high-intensity exercise. RFR_angina similarly increased from 0.22 (IQR, 0.16-0.30) at rest to 0.26 (IQR, 0.18-0.36) and 0.32 (IQR, 0.23-0.46) during low- and high-intensity exercise. All thresholds were significantly lower than clinical diagnostic cut points (<i>P</i><0.001). Lower FFR_angina and RFR_angina thresholds were associated with greater symptom reproducibility across rest, low- and high-intensity exercise conditions (FFR_angina: <i>P</i>=0.008, <i>P</i><0.001, <i>P</i><0.001, respectively; RFR_angina: <i>P</i>=0.015, <i>P</i><0.001, <i>P</i>=0.002, respectively). Lower angina thresholds across all conditions predicted higher baseline angina burden and greater symptom relief with PCI (<i>P</i>_interaction>0.999).</p><p><strong>Conclusions: </strong>Physiological thresholds for angina (FFR_angina and RFR_angina) are highly individualized, vary with cardiac workload, and are consistently lower than the universal ischemia-based thresholds used to guide revascularization. These findings support integrating personalized, symptom-linked physiology to refine patient selection and to improve symptomatic response to PCI.</p>","PeriodicalId":10331,"journal":{"name":"Circulation","volume":" ","pages":""},"PeriodicalIF":38.6,"publicationDate":"2026-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147834437","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":"GPRASP1 Safeguards Endothelial Aspartate Metabolism to Prevent Pulmonary Hypertension Associated With Heart Failure With Preserved Ejection Fraction.","authors":"Ruofei Li, Yushan Tang, Yuqin Ding, Pengyan Hu, Cheng Lv, Xiayidan Alimu, Xiaoyi Wei, Xiaojian Wang, Miaoqing Hu, Yanan Zhang, Yu Zhang, Yibo Wang","doi":"10.1161/CIRCULATIONAHA.126.079030","DOIUrl":"https://doi.org/10.1161/CIRCULATIONAHA.126.079030","url":null,"abstract":"<p><strong>Background: </strong>Pulmonary hypertension (PH) is a serious complication of heart failure with preserved ejection fraction (HFpEF), for which no targeted therapies are currently available. Endothelial dysfunction plays a crucial role in PH associated with HFpEF (PH-HFpEF), yet its molecular drivers remain poorly defined.</p><p><strong>Methods: </strong>Transcriptome profiling uncovered endothelial characteristics of PH-HFpEF. Endothelial-specific GPRASP1 (GPCR [G protein-coupled receptor]-associated sorting protein 1 deletion in mice was conducted to investigate its participation in PH-HFpEF pathology. Multimodal metabolomics, isotope tracing, proteomics, and mechanistic biochemical assays were used to map downstream pathways and identify druggable mediators.</p><p><strong>Results: </strong>GPRASP1 was significantly lowered in pulmonary endothelial cells of PH-HFpEF models. Endothelial <i>Gprasp1</i> knockout mice exhibited major PH-HFpEF features, including pulmonary vascular remodeling, elevated pulmonary pressure, diastolic dysfunction, and abnormal glucose/lipid metabolism. GPRASP1 loss impaired tricarboxylic acid cycle activity by stabilizing ASNS (asparagine synthetase), preferentially shifting aspartate toward asparagine synthesis over oxaloacetate production. This metabolic reprogramming led to adenosine triphosphate depletion, reactive oxygen species accumulation, endothelial nitric oxide synthase uncoupling, and nitric oxide deficiency. We discovered that, beyond its classic role in GPCR sorting, GPRASP1 functioned as a noncanonical adaptor protein that scaffolded the E3 ubiquitin ligase PKN (Parkin) and ASNS, promoting PRKN-dependent K48-linked ubiquitination and proteasomal degradation of ASNS via its C-terminal domain. In parallel, under mitochondrial stress, GPRASP1 strengthened PRKN interactions with MFN1/2, enhanced their K63-linked ubiquitination, and facilitated PRKN-mediated mitophagy. Restoration of GPRASP1 expression or pharmacological inhibition of ASNS activity with olopatadine normalized aspartate utilization, improved mitochondrial bioenergetics, rescued endothelial function, and attenuated cardiopulmonary pathology in PH-HFpEF models.</p><p><strong>Conclusions: </strong>Our findings unlocked a noncanonical role of GPRASP1 in preserving pulmonary endothelial homeostasis and delineated a novel GPRASP1-PRKN-ASNS axis that connected proteostasis with endothelial metabolic integrity, highlighting aspartate metabolism as a targetable vulnerability in cardiopulmonary disease.</p>","PeriodicalId":10331,"journal":{"name":"Circulation","volume":" ","pages":""},"PeriodicalIF":38.6,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147834388","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":"CD40-TRAF2/3/5 Signaling Promotes Cardiac Repair by Mediating Macrophage Efferocytosis After Myocardial Infarction.","authors":"Linlin Zhang, Yanshan Chen, PengPeng Xu, Tao Zheng, Jie Sheng, Zhiyue Wang, Sheng Wang, Yu Ding, Jiaqi Lu, Xingji Liu, Canbiao Wang, Yunming Zhang, Long Ma, Jing Pan, Jun Pu, Longjiang Zhang","doi":"10.1161/CIRCULATIONAHA.125.078873","DOIUrl":"https://doi.org/10.1161/CIRCULATIONAHA.125.078873","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;After myocardial infarction (MI), macrophage-mediated clearance of dead cells, a process known as efferocytosis, represents a pivotal role in tissue remodeling. Efficient efferocytosis contributes to rescuing neighboring viable cardiomyocytes, drives the phenotypic transition of reparative macrophages, and facilitates the resolution of inflammation. In this study, we explored the roles of CD40 and the signals transduced by its 2 downstream adaptor-protein binding sites (TRAF2/3/5 and TRAF6) in the cardiac macrophage efferocytosis after MI.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Systemic, myeloid- and macrophage-specific CD40-deficient mice were used to determine the functional significance of CD40 during post-MI repair. The effects of CD40 on macrophages functional states were evaluated with single-cell RNA sequencing. Flow cytometry, immunofluorescence staining, Western blot, and ELISA were used to assess the efferocytosis and inflammatory status of macrophages after MI. CD40-TRAF2/3/5&lt;sup&gt;-/-&lt;/sup&gt; and CD40-TRAF6&lt;sup&gt;-/-&lt;/sup&gt; mice were used to explore the roles of CD40 downstream signaling intermediates in MI and macrophage efferocytosis.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;The expression level of CD40 was increased remarkably from 3 to 7 days after MI. Myeloid-derived macrophages emerged as the dominant population expressing CD40. CD40 deficiency resulted in an augmented infarct size and compromised cardiac function after MI. Further investigations demonstrated that CD40 deficiency led to a notable decline in macrophage efferocytosis, which is associated with a reduced abundance of cluster 0 cells, identified by single-cell RNA sequencing, representing the precursor of reparative macrophages. Moreover, single-cell RNA sequencing indicated that CD40&lt;sup&gt;+&lt;/sup&gt; macrophages could be classified primarily into 2 distinct cell subsets: 1 subset was associated mainly with efferocytosis functions, and the other was involved predominantly in immune-inflammatory responses. Direct activation of CD40 failed to upregulate macrophage efferocytosis but instead induced a proinflammatory state. These implied differential effects of the signals transduced by the 2 TRAF binding sites (TRAF2/3/5 and TRAF6) downstream of CD40 on efferocytosis. Findings from CD40-TRAF2/3/5&lt;sup&gt;-/-&lt;/sup&gt; and CD40-TRAF6&lt;sup&gt;-/-&lt;/sup&gt; mice confirmed that the CD40-TRAF2/3/5 signaling served as a crucial determinant in mediating CD40-related efferocytosis. STAT6 was identified as a key downstream factor in this process. Adenovirus-mediated gene transfer to overexpress a CD40 variant retaining TRAF2/3/5 binding site but lacking the TRAF6 in cardiac macrophages led to improvements in cardiac function and macrophage efferocytosis after MI.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;Our study established a pivotal positive role of macrophage CD40 in post-MI repair by facilitating macrophage efferocytosis. Specifically, TRAF2/3/5 rather than TRAF6 serves as the crucial signal","PeriodicalId":10331,"journal":{"name":"Circulation","volume":" ","pages":""},"PeriodicalIF":38.6,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147834447","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":"Implications of Cranial Arterial Stenosis and Dolichoectasia for Cerebral Small-Vessel Disease Etiopathogenesis: Findings From a Prospective Mild Stroke Cohort.","authors":"Fei Han, Una Clancy, Carmen Arteaga-Reyes, Michael J Thrippleton, Maria Del C Valdés Hernández, Daniela Jaime Garcia, Michael S Stringer, Ellen Backhouse, Francesca M Chappell, Yajun Cheng, Dillys Xiaodi Liu, Junfang Zhang, Angela C C Jochems, Eleni Sakka, Charlotte Jardine, Gayle Barclay, Donna McIntyre, Iona Hamilton, Rosalind Brown, Yi-Cheng Zhu, Fergus N Doubal, Joanna M Wardlaw","doi":"10.1161/CIRCULATIONAHA.126.079493","DOIUrl":"https://doi.org/10.1161/CIRCULATIONAHA.126.079493","url":null,"abstract":"<p><strong>Background: </strong>Stenosis and dolichoectasia of cranial arteries likely reflect distinct mechanisms. Their contributions to lacunar stroke and cerebral small-vessel disease (cSVD) remain contentious. We investigated the associations of large-artery stenosis (LAS) and arterial widening with stroke subtype, cSVD markers, incident infarcts, and clinical outcomes.</p><p><strong>Methods: </strong>We prospectively recruited patients with lacunar or mild nonlacunar stroke, with demographic, stroke-related, cognitive, functional, and magnetic resonance imaging (index and incident infarcts, cSVD markers) assessments at baseline and 1 year. LAS was defined as ≥50% intracranial or cervical artery stenosis; basilar artery dolichoectasia was defined by basilar artery diameter, bifurcation height, and lateral displacement; and intracranial carotid and middle cerebral artery diameters were also measured. Associations were estimated from multivariable logistic, linear, and proportional odds regression models adjusted for age, sex, and vascular risk factors. We further conducted a systematic literature review to synthesize evidence on relationships between large-artery pathology and cSVD.</p><p><strong>Results: </strong>Among 229 patients (mean age, 65.9±11.1 years; 131 [57.2% ] lacunar stroke), LAS and basilar artery dolichoectasia were present in 20.5% and 15.7%, respectively. After adjustment, LAS (odds ratio, 0.49 [95% CI, 0.23-0.99]) and the presence of any embolic source were associated with lower odds of lacunar versus non-lacunar stroke, and not with cSVD markers or incident infarcts. In contrast, basilar artery dolichoectasia was strongly associated with lacunar stroke (odds ratio, 4.67 [95% CI, 1.87-13.14]), higher cSVD scores (ordinal analysis; odds ratio, 2.57 [95% CI, 1.28-5.25]), incident infarcts (75% subcortical; odds ratio, 2.29 [95% CI, 1.01-5.14]), and greater progression of white matter hyperintensities over 1 year (β, 0.15 [95% CI, 0.01-0.29] per log10-transformed volume). Similar associations were observed for wider intracranial arteries. The systematic review supported these findings.</p><p><strong>Conclusions: </strong>cSVD, including lacunar stroke, was unrelated to LAS but strongly associated with dolichoectasia and wider arteries. These findings support a nonatheromatous, intrinsic microvascular pathology, particularly segmental arteriolar disorganization, as the principal mechanism of lacunar stroke and cSVD. Mechanism-specific diagnostic and therapeutic strategies are warranted.</p>","PeriodicalId":10331,"journal":{"name":"Circulation","volume":" ","pages":""},"PeriodicalIF":38.6,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147834382","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":"Vascular Aging.","authors":"Ruoqi Wang, Stephen Y Chan, Toren Finkel","doi":"10.1161/CIRCULATIONAHA.125.075567","DOIUrl":"https://doi.org/10.1161/CIRCULATIONAHA.125.075567","url":null,"abstract":"<p><p>Vascular aging is a central determinant of healthy life span, not only influencing the susceptibility to cardiovascular diseases but also shaping the risk of systemic decline across multiple organs. It is driven by a variety of age-related factors, including cellular senescence, chronic inflammation, loss of proteostasis, mitochondrial dysfunction, genomic instability, epigenetic remodeling, and stem cell exhaustion. These processes interact with the unique mechanical and metabolic environment of the vasculature to create a distinctive pathological trajectory, manifested in part as arterial stiffening, impaired barrier integrity, and dysregulated vasomotor control. Recent advances in single-cell omics and cross-organ molecular clocks have revealed the heterogeneity and organ specificity of aging, underscoring the need for integrative frameworks that connect vascular biology with overall health. Meanwhile, the development of diverse therapeutic strategies-ranging from senolytic and immune-mediated clearance to metabolic and mitochondrial interventions-highlights the translational potential of targeting the aging vasculature. Looking ahead, multimodal biomarkers and precision medicine may transform vascular aging from an inevitable process into a modifiable determinant of health span.</p>","PeriodicalId":10331,"journal":{"name":"Circulation","volume":"153 18","pages":"1421-1435"},"PeriodicalIF":38.6,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147834421","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":"Letter by Yang and Wu Regarding Article, \"Ivabradine in Patients Undergoing Noncardiac Surgery: A Randomized Controlled Trial\".","authors":"Xiaoting Yang, Hui Wu","doi":"10.1161/CIRCULATIONAHA.125.077683","DOIUrl":"https://doi.org/10.1161/CIRCULATIONAHA.125.077683","url":null,"abstract":"","PeriodicalId":10331,"journal":{"name":"Circulation","volume":"153 18","pages":"e1281-e1282"},"PeriodicalIF":38.6,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147834391","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":"Intermediate Effect Variants in HCM: Integration into Clinical Practice and Family Screening.","authors":"Roddy Walsh, Pablo Garcia-Pavia, Juan Pablo Ochoa","doi":"10.1161/CIRCULATIONAHA.125.077435","DOIUrl":"https://doi.org/10.1161/CIRCULATIONAHA.125.077435","url":null,"abstract":"","PeriodicalId":10331,"journal":{"name":"Circulation","volume":"153 18","pages":"1347-1349"},"PeriodicalIF":38.6,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147834377","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":"A New Right Bundle Branch Block-Like Rhythm Immediately After TAVR.","authors":"Jun-Peng Liu, Nan Chen, Hui-Ping Zhang","doi":"10.1161/CIRCULATIONAHA.126.080374","DOIUrl":"https://doi.org/10.1161/CIRCULATIONAHA.126.080374","url":null,"abstract":"","PeriodicalId":10331,"journal":{"name":"Circulation","volume":"153 18","pages":"1436-1438"},"PeriodicalIF":38.6,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147834418","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":"Daily Stellate Ganglion Phototherapy for Ventricular Arrhythmias: A Noninvasive Neuromodulation Approach for Outpatient Care.","authors":"Yoshihiro Harano, Yasutoshi Shinoda, Yuto Iioka, Yuka Oda, Yuichi Hanaki, Hiro Yamasaki, Miyako Igarashi, Tomoko Ishizu, Akihiko Nogami, Yuki Komatsu","doi":"10.1161/CIRCULATIONAHA.125.078175","DOIUrl":"https://doi.org/10.1161/CIRCULATIONAHA.125.078175","url":null,"abstract":"","PeriodicalId":10331,"journal":{"name":"Circulation","volume":"153 18","pages":"1439-1441"},"PeriodicalIF":38.6,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147834372","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":"Letter by Lu et al Regarding Article, \"Ivabradine in Patients Undergoing Noncardiac Surgery: A Randomized Controlled Trial\".","authors":"Youyi Lu, Lin Li, Qi Li","doi":"10.1161/CIRCULATIONAHA.125.077593","DOIUrl":"https://doi.org/10.1161/CIRCULATIONAHA.125.077593","url":null,"abstract":"","PeriodicalId":10331,"journal":{"name":"Circulation","volume":"153 18","pages":"e1279-e1280"},"PeriodicalIF":38.6,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147834403","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}