Multicenter Cohort Research Articles

Plasma Phenylacetylglutamine Levels and Prognosis of Ischemic Stroke: A Multicenter Prospective Study Based on the CATIS Trial.

Phenylacetylglutamine is implicated in platelet clotting and thrombosis, but its prognostic value in ischemic stroke remains unclear. We aimed to explore the associations of plasma phenylacetylglutamine levels with adverse outcomes after ischemic stroke in a multicenter prognostic cohort study. Our multicenter prognostic cohort study included 3564 Chinese patients with ischemic stroke from the CATIS (China Antihypertensive Trial in Acute Ischemic Stroke). All patients were followed up at 3 months after ischemic stroke onset. The primary outcome was the composite outcome of death or major disability (modified Rankin Scale score, 3-6) at 3 months after ischemic stroke. During 3 months of follow-up, 877 participants experienced the primary outcome. After multivariate adjustment, each 500 ng/mL increase of phenylacetylglutamine was associated with a 7% (P=0.012), 6% (P=0.016), and 6% (P=0.028) increased risk of the primary outcome, major disability, and death, respectively. The odds ratios or hazard ratios in the highest versus the lowest quartile of plasma phenylacetylglutamine were 1.62 ([95% CI, 1.18-2.23]; Ptrend=0.001) for the primary outcome, 1.62 ([95% CI, 1.16-2.24]; Ptrend=0.001) for major disability, and 2.59 ([95% CI, 1.19-5.60]; Ptrend=0.025) for death, respectively. There was a significantly worse shift in the distribution of modified Rankin Scale score at 3 months with higher phenylacetylglutamine quartiles (Ptrend=0.003). Multiple-adjusted spline regression model showed a linear relationship between phenylacetylglutamine and primary outcome (P value for linearity<0.001). The addition of plasma phenylacetylglutamine to conventional risk factors significantly improved the risk reclassification for the primary outcome (net reclassification improvement, 19.34%; P<0.001; integrated discrimination improvement, 0.23%; P=0.019). Elevated plasma phenylacetylglutamine levels at baseline were associated with increased risks of adverse clinical outcomes at 3 months after ischemic stroke, suggesting that phenylacetylglutamine may be a promising prognostic biomarker for ischemic stroke. Further studies are needed to investigate whether phenylacetylglutamine is a stroke-specific biomarker.

Integrated single-cell transcriptomic analyses identify a novel lineage plasticity-related cancer cell type involved in prostate cancer progression

Cancer cell plasticity is the ability of neoplastic cells to alter their identity and acquire new biological properties under microenvironmental pressures. In prostate cancer (PCa), lineage plasticity often results in therapy resistance and trans-differentiation to neuroendocrine (NE) lineage. However, identifying the cancer cells harboring lineage plasticity-related status remains challenging. Based on 13 multi-center human PCa bulk transcriptomic cohorts (samples=3314) and 9 bulk transcriptomic datasets derived from PCa experimental models, we established an integrated lineage plasticity-related gene signature, termed LPSig. Leveraging this gene signature, AUCell enrichment analysis was applied to identify the cell population with high lineage plasticity from a comprehensive single-cell RNA-sequencing (scRNA-seq) meta-atlas assembled by us, which consisted of 10 public human PCa scRNA-seq datasets (samples=93, cells=222,529). Moreover, additional scRNA-seq dataset of human PCa, multiplex immunohistochemistry staining for human PCa tissues, invitro and invivo functional experiments, as well as qPCR and Western blot analyses were employed to validate our findings. We found that LPSig could finely capture the dynamics of tumor lineage plasticity throughout the progression of PCa, accurately estimating the status of lineage plasticity. Based on LPSig, we identified a previously undefined minority population of lineage plasticity-related PCa cells (LPCs) from the human PCa scRNA-seq meta-atlas assembled by this study. Furthermore, in-depth dissection revealed pivotal roles of LPCs in trans-differentiation, tumor recurrence, and poor patient survival during PCa progression. Furthermore, we identified HMMR as a representative cell surface marker for LPCs, which was validated using additional scRNA-seq datasets and multiplexed immunohistochemistry. Moreover, HMMR was transcriptionally inhibited by androgen receptor (AR), and was required for the aggressive adenocarcinoma features and NE phenotype. Our study uncovers a novel population of lineage plasticity-related cells with low AR activity, stemness-like traits, and elevated HMMR expression, that may facilitate poor prognosis in PCa. This work was supported by National Key R&D Program of China (2022YFA0807000), National Natural Science Foundation of China (82160584), Advanced Prostate Cancer Diagnosis and Treatment Technology Innovation Team of Kunming Medical University (CXTD202216), and Reserve Talents of Young and Middle-aged Academic Leaders in Yunnan Province (202105AC160013).

Plasma proteomic signatures of liver steatosis and fibrosis in people living with HIV: a cross-sectional study

Insights into the mechanisms driving metabolic dysfunction-associated steatotic liver disease (MASLD) in people living with HIV (PLHIV) remain limited. Plasma proteomics holds promise for biomarker discovery and the elucidation of biological mechanisms. We performed cross-sectional analyses on data from 1036 virally suppressed PLHIV using antiretroviral treatment (ART) from the Dutch multi-centre 2000HIV cohort. Participants underwent transient elastography to assess liver steatosis (controlled attenuation parameter (CAP)≥263dB/m) and -fibrosis (liver stiffness measurement (LSM)≥7.0kPa). Plasma protein concentrations (n=2367) (Olink® Explore Panel) were compared between PLHIV with vs. without liver steatosis and PLHIV with vs. without fibrosis. Enriched pathways (using GO, KEGG and Reactome libraries) and correlations with clinical characteristics wereassessed, and analyses were stratified by BMI category. In addition, concentrations of 242 proteins werecompared between individuals ("controls") with and without liver steatosis (ratio of methylene:methylene and water >5.6% on magnetic resonance spectroscopy) from a separate cohort (300-OB), all having a BMI >26kg/m2. Steatosis and fibrosis were associated with 67/2367 (2.2%) and 17/2367 (0.7%) differentially expressed proteins (DEP), respectively, enriched in mostly metabolic pathways. Immunoglobulin superfamily member 9 (IGSF9) was amongst the top DEP associated with both steatosis and fibrosis. Stratifying by BMI revealed 8/2367 DEP associated with steatosis in lean- and 12/2367 DEP in overweight/obese individuals, with two shared DEP (IGSF9 and GHR). Conversely, protein signatures of overweight/obese PLHIV (32/242 DEP) and overweight/obese HIV-uninfected individuals (32/242 DEP) exhibited substantial overlap with 16 shared DEP. Notably, DEP correlated with HIV characteristics in lean individuals but not in overweight/obese PLHIV. Lean and overweight/obese PLHIV exhibit distinct proteomic signatures associated with liver steatosis, with the former being more strongly correlated with HIV-specific factors and ART. In addition, we identified a protein, IGSF9, strongly related to liver fibrosis and steatosis across BMI categories. The 2000HIV study is funded by ViiV Healthcare.

Anti-interferon gamma-inducible protein 16 antibodies: Identification of a novel autoantigen in idiopathic interstitial pneumonia and its clinical characteristics based on a multicenter cohort study

Autoantibodies are detected in idiopathic interstitial pneumonias (IIPs) without a clear connective tissue disease diagnosis, and their clinical significance is unclear. This study aimed to identify a novel autoantibody in IIPs. We screened 295 IIP patients using a 35S-methionine labeled protein immunoprecipitation assay. Candidate autoantigens were identified via protein array and confirmed by immunoprecipitation. Six sera from 295 IIP patients immunoprecipitated common tetrameric proteins (100 kDa). The protein array identified interferon gamma-inducible protein 16 (IFI16) as the candidate autoantigen. Patients with anti-IFI16 antibodies received immunosuppressants less frequently. Five-year survival rates were 50 %, 69 %, and 63 % (P = 0.60), and acute exacerbation-free rates were 50 %, 96 %, and 84 % (P = 0.15) for patients with anti-IFI16, anti-aminoacyl tRNA antibodies, and others. Anti-IFI16 is a novel autoantibody in IIPs. Patients with this antibody often receive less immunosuppressive therapy and could have a poor prognosis. Further research is needed to refine patient stratification and management.

Tissue Kallikrein Supplementation in Ischemic Phase Protects the Neurovascular Unit and Attenuates Reperfusion-Induced Injury in Ischemic Stroke

Tissue kallikrein (TK) has emerged as a potential neuroprotective agent in ischemic stroke (IS), yet the optimal timing and mechanisms of TK therapy remain unclear. Here, we established a causal link between lower baseline TK levels and an increased risk of stroke through a retrospective, multicenter cohort study involving 2,115 initially non-stroke subjects monitored for 5 years. Sequentially, we observed a notable increase in bradykinin receptor 2 (B2R) levels during the ischemic phase of the IS model, while levels of TK and bradykinin receptor 1 (B1R) remained stable. Intriguingly, both B1R and B2R exhibited a significant elevation 24hours after reperfusion. Further investigations in preclinical models demonstrated that TK supplementation activates the PI3K/AKT signaling pathway via enhanced B2R expression during the ischemic phase, leading to nuclear translocation of Hif-1α. This activation enhances the expression of VEGF and eNOS, thereby fortifying the neurovascular unit. Moreover, it suppresses the activation of the kallikrein-kinin system induced by reperfusion injury, effectively reducing inflammation, ROS production, apoptosis, and endothelial barrier dysfunction. Thus, our findings highlight the significance of TK supplementation during the ischemic phase in attenuating reperfusion-induced injury in IS, providing a mechanistic rationale for determining the optimal timing for TK supplementation therapy.

Lung Ultrasound in the Acute Phase of ST-Segment-Elevation Acute Myocardial Infarction: 1-Year Prognosis and Improvement in Risk Prediction.

Lung ultrasound (LUS) has emerged as a useful tool in the acute phase of patients admitted for ST-segment-elevation myocardial infarction. However, its long-term significance remains uncertain, and risk scores do not include LUS findings as a predictor. This study aims to assess the 1-year prognostic value of LUS and its ability to enhance existing risk scores. This is a multicenter prospective cohort study involving 373 patients with ST-segment-elevation myocardial infarction. LUS was performed during the first 24 hours after angiography. LUS results were assessed both as a categorical (wet/dry lung) and continuous variable (LUS score). The primary end point comprised the following major adverse cardiovascular events: all-cause mortality or hospitalization for heart failure, acute coronary syndrome, or stroke within 1 year. We also evaluated whether LUS could enhance the predictive value of the GRACE (Global Registry of Acute Coronary Events) score. Major adverse cardiovascular events occurred in 51 (13.7%) patients over a median follow-up of 368 days. After multivariate analysis, the LUS score was an independent predictor (hazard ratio [HR], 1.06 [95% CI, 1.01-1.10]; P=0.009] for each additional B-line), whereas the categorical classification was an independent predictor in patients with ST-segment-elevation myocardial infarction Killip I (HR, 3.12 [95% CI, 1.34-7.31]; P=0.009). Incorporating LUS into GRACE resulted in a net reclassification index of 31.6% and a significant increase in the area under the curve; GRACE alone scored 0.705 compared with GRACE+LUS 0.791 (P=0.002). Detecting B-lines on LUS at the acute phase predicts major adverse cardiovascular events at 1 year in patients with ST-segment-elevation myocardial infarction and enhances the predictive value of the GRACE score. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04526535.

Airway Mucus Plugs on Chest Computed Tomography Are Associated with Exacerbations in COPD.

Mucus plugs were visually-identified on baseline chest computed tomography (CT) scans from smokers with Global Initiative for Chronic Obstructive Lung Disease (GOLD) grades 2-4 COPD enrolled in two multicenter cohort studies: Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) and COPDGene. Associations between ordinal mucus plug score categories (0/1-2/≥3) and prospectively-ascertained AEs, defined as worsening respiratory symptoms requiring systemic steroids and/or antibiotics (moderate-to-severe) and/or ER/hospitalization (severe), were assessed using multivariable-adjusted zero-inflated Poisson regression; subjects were exacerbation-free at enrollment. Among 3,250 participants in COPDGene (mean±SD age 63.7±8.4 years, FEV1 50.6%±17.8% predicted, 45.1% female) and 1,716 participants in ECLIPSE (age 63.3±7.1 years, FEV1 48.3%±15.8% predicted, 36.2% female), 44.4% and 46.0% had mucus plugs, respectively. The incidence rates of AEs were 61.0 (COPDGene) and 125.7 (ECLIPSE) per 100 person-years. Relative to those without mucus plugs, the presence of 1-2 and ≥3 mucus plugs was associated with increased risk (adjusted rate ratio, aRR [95%CI]=1.07[1.05-1.09] and 1.15[1.1-1.2] in COPDGene; aRR=1.06[1.02-1.09] and 1.12[1.04-1.2] in ECLIPSE, respectively) for prospective moderate-to-severe AEs. The presence of 1-2 and ≥3 mucus plugs was also associated with increased risk for severe AEs during follow-up (aRR=1.05[1.01-1.08] and 1.09[1.02-1.18] in COPDGene; aRR=1.17[1.07-1.27] and 1.37[1.15-1.62] in ECLIPSE, respectively). CT-based mucus plugs are associated with an increased risk for future COPD AEs.

Prognosis and Risks for Probable Chronic Lung Allograft Dysfunction: A Prospective Multicenter Study.

Chronic lung allograft dysfunction (CLAD) hinders lung transplant success. A 2019 consensus refined CLAD diagnosis, introducing probable or definite CLAD based on persistence of lung function decline. Outcomes and risks for probable CLAD remain uncertain. Determine the prognosis and clinical risks for probable CLAD in a prospective multicenter cohort. Clinical Trials in Organ Transplantation-20 included 745 CLAD-eligible adult lung recipients at 5 centers and applied rigorous methods to prospectively adjudicate probable CLAD. The impact of probable CLAD on graft loss was determined using a Cox model that considered CLAD as a time-dependent covariate. Regularized Cox modeling with LASSO penalty was used to evaluate donor or recipient characteristics and the occurrence and timing of posttransplant events as probable CLAD risks. Similar analyses were performed for definite CLAD. Probable CLAD occurred in 29.7% of patients at 3 years posttransplant and conferred a marked increase in risk for graft loss (unadjusted HR 4.38, p<0.001). Most patients (80%) with probable CLAD progressed to definite CLAD. Cytomegalovirus infection and specifically late presence (>90 days posttransplant) of donor-specific alloantibodies, acute rejection, acute lung injury, or organizing pneumonia contributed the greatest independent information about probable CLAD risk. Definite CLAD risks were similar. Probable CLAD identifies patients at high risk for graft loss, supporting prospective identification of this condition for early initiation of CLAD-directed interventions. More effective strategies to prevent posttransplant cytomegalovirus, inhibit allospecific immunity, and reduce tissue injury are needed to reduce probable CLAD and improve lung recipient survival.

High incidence of malignant arrhythmias and heart failure in patients with RBM20-associated cardiomyopathy: a multicenter cohort study and review of the literature

Abstract Background Patients with RBM20 cardiomyopathy commonly experience malignant arrhythmias, sudden cardiac death (SCD), and progressive heart failure (HF). Objective The aim of this study is to investigate genotype-phenotype correlations, clinical outcomes and causes of death in patients with RBM20-associated cardiomyopathy in a multicenter cohort, combined with an overview of the current literature. Methods This international, multicenter cohort included all patients with cardiomyopathy who had a pathogenic (P) or likely pathogenic (LP) RBM20 variant. For survival and regression analysis, we matched a control group based on sex, age, and presence of left ventricular dysfunction. Additionally, we conducted a literature search on studies investigating RBM20-associated cardiomyopathy. Results Sixty-two patients (45% male) were included in the study, with a mean age of 42 ± 15 years at presentation. Of the LP/P RBM20 variants identified, 9 were novel. Eleven variants were truncating, while the remaining variants consisted of missense and splice-site variants. Patients with a truncating variant who developed HF were on average older at the time of diagnosis compared to patients with missense variants (mean age 62 ± 9 vs. 45 ± 14; p=0.01). After a median follow-up duration of 5.0 [1.0 – 10.5] years, 21 (34%) patients reached the composite endpoint of ventricular arrhythmias (VA), implantable cardioverter-defibrillator therapy, heart transplantation (HTx), left ventricular assist device (LVAD) implantation, or cardiovascular death. Of these, 19 (31%) patients experienced malignant VA (mean age 45 ± 15 years, 63% males). Males were at higher risk for the composite endpoint (log-rank p= 0.02), particularly for VA (log-rank p=0.007). The literature review analyzed 34 studies with a total of 678 patients, of whom 53% were male. In these studies, 123 (24%) patients experienced a VA, 58 (12%) underwent HTx or were treated with LVAD, and 52 (11%) died. Conclusion In this multicenter study the patients carrying a LP/P variant in RBM20 variants had a severe phenotype, with a high incidence of VA, particularly in males. Additionally, this study presents 9 novel DNA variants, of which 8 were truncating, and were mainly observed in older individuals. Finally, we report a lower mortality rate compared to the literature, possibly due to a higher number of heart transplantations performed in our patient cohort.Survival composite endpoint for sex

ABLE-SCORE: a simplified risk score for major adverse cardiovascular outcomes in patients with left ventricular noncompaction

Abstract Background Left ventricular noncompaction (LVNC) is a heterogeneous entity with life-threatening complications and variable prognosis [1,2]. However, there are limited prediction models available to identify individuals at high risk of adverse outcomes, and the current risk score in LVNC is comparatively complex for clinical practice [3,4]. Purpose To develop and validate a simplified risk score to predict major adverse cardiovascular events (MACE) in LVNC. Methods This multicenter longitudinal cohort study consecutively enrolled morphologically diagnosed LVNC patients between January 2009 and December 2020 at a single national-level medical center (derivation cohort n=300; internal validation cohort n=129), and between January 2014 and December 2022 at two national-level medical centers (external validation cohort n=95). The derivation/internal validation cohorts and the multicenter external validation cohort were followed annually until December 2022 and December 2023, respectively. MACE was defined as a composite of all-cause mortality, heart transplantation/left ventricular assist device implantation, cardiac resynchronization therapy, malignant ventricular arrhythmia, and thromboembolism. A simplified risk score, the ABLE-SCORE, was developed based on independent risk factors for MACE in the multivariable Cox regression predictive model, and underwent both internal and external validation to confirm its discrimination (Harrell’s C-index), calibration (calibration plots), and clinical applicability (decision curve analysis). Results A total of 524 LVNC patients (43.5 ± 16.6 years, 65.8% male) were included in the study. At the end of the follow-up, 97 (32.3%), 38 (29.5%), and 20 (21.1%) individuals in the derivation, internal validation, and external validation cohort experienced at least one endpoint of MACE. The ABLE-SCORE was established using four easily accessible clinical variables: age at diagnosis, N-terminal pro-brain natriuretic peptide levels, left atrium enlargement and left ventricular ejection fraction≤40% measured by echocardiography. The risk score showed excellent performance in discrimination, with Harrell’s C-index of 0.821 (95%CI 0.772-0.869), 0.786 (95%CI 0.703-0.869), and 0.750 (95%CI 0.644-0.856) in the derivation, internal validation, and external validation cohort, respectively. Calibration plots of the three datasets suggested accurate agreement between the predicted and observed 5-year risk of MACE in LVNC. According to decision curve analysis, the ABLE-SCORE displayed greater net benefit than the currently existing risk score for MACE in LVNC [3], indicating its strength in clinical applicability. Conclusions Derived from readily available laboratory and echocardiographic variables, a simplified and efficient risk score for MACE was developed and validated using a large LVNC cohort, making it a reliable and convenient tool for the risk stratification and clinical management of patients with LVNC.Development of the ABLE-SCOREValidation of the ABLE-SCORE

Improving the prediction of major adverse cardiovascular events in patients with hypertrophic cardiomyopathy by adding plasma SVEP1 to conventional clinical model including NT-proBNP

Abstract Background Hypertrophic cardiomyopathy (HCM) is the most common genetic heart disease with a prevalence between 1 in 200 to 500 [1]. HCM can lead to major adverse cardiovascular events (MACE) such as heart failure (HF) hospitalization and cardiac death [2,3]. A protein named "sushi, von Willebrand factor type A, EGF and pentraxin domain containing 1" (SVEP1) is a large extracellular matrix protein whose activity can be measured in plasma [4,5]. SVEP1 promotes inflammation and atherosclerosis [4,5]. SVEP1 is associated with risk of HF hospitalization and cardiac death in patients with HF with reduced ejection fraction [6]. However, no prior study has assessed the prognostic value of SVEP1 in patients with HCM. Purpose To test the hypothesis that the addition of SVEP1 improves the predictive performance of the conventional model based on clinical risk factors plus NT-proBNP for future MACE in patients with HCM. Methods We performed a multicenter prospective cohort study of patients with HCM [7]. The outcome was MACE, defined as a composite of HF hospitalization or cardiac death [6]. After dividing the cohort into four groups using the median values of SVEP1 and NT-proBNP, we compared the risk of the outcome event using the Cox proportional hazards model adjusting for 15 clinical risk factors known to be associated with MACE in HCM (Figure 1) [8-11]. We also developed the Lasso-regularized Cox proportional hazards model to predict the time to first MACE by adding SVEP1 to the 15 clinical risk factors with or without NT-proBNP in the training cohort (randomly selected 75% of the cohort). We then compared the predictive performance in the test cohort (25% of the cohort) using the C-statistic of each model. Results During a median follow-up of 1.9 (25 percentile-75 percentile, 0.7-4.3) years, the outcome event occurred in 63 (10%) of 610 patients. The four groups stratified by the median of SVEP1 and NT-proBNP levels had different risks of the outcome event (log-rank p&amp;lt;0.001: Figure 1). Even in the groups with lower-than-median NT-proBNP levels, the high-SVEP1 group had higher risks of MACE compared with the low-SVEP1 group (adjusted hazard ratio 4.52, p=0.042: Figure 1). In the prediction of time to first MACE, the addition of SVEP1 improved the C-statistic of the clinical model (p&amp;lt;0.001) and that of the clinical plus NT-proBNP model (p=0.01: Figure 2). The clinical plus SVEP1 model also outperformed the clinical plus NT-proBNP model (p=0.005: Figure 2). Conclusions In the present multicenter prospective cohort study of 610 patients with HCM, SVEP1 improved MACE risk stratification when added to the conventional model consisting of clinical risk factors plus NT-proBNP. SVEP1 also exhibited a superior predictive ability than NT-proBNP to predict MACE in patients with HCM. These data collectively indicate that SVEP1 provides additional risk stratification and may be a better biomarker than NT-proBNP for the prognostication of patients with HCM.Figure 1.Kaplan-Meier curves for MACEFigure 2.Time-dependent AUROC curves

The association of steatotic liver disease with recurrent ischemic events in patients with chronic coronary syndrome: a multicenter cohort study

Abstract Background/introduction A panel of multi-society experts has proposed new subcategories under the term steatotic liver disease (SLD), replacing the exclusive term non-alcoholic fatty liver disease with the new nomenclature metabolic dysfunction-associated steatotic liver disease (MASLD). However, the prognostic impact of SLD subtypes in patients with chronic coronary syndrome (CCS) remains unknown. Purpose We aimed to investigate the associations between SLD subtypes and recurrent event risks in CCS patients. Methods Our analysis included a total of 9,448 patients with CCS from a large multicenter nationwide cohort. Hepatic steatosis was defined as hepatic steatosis index ≥36 and ultrasound evidence. Patients were categorized into four groups based on the evidence of steatosis, cardiometabolic risk factors and alcohol intake: 1) no SLD; 2) MASLD; 3) MASLD with increased alcohol intake (MetALD) and 4) SLD with other causes. The primary outcome was major adverse cardiac and cerebrovascular events (MACCE), a composite of all-cause mortality, myocardial infarction, stroke and unplanned revascularization. Results The prevalence of no SLD, MASLD, MetALD and SLD with other causes in our population was 37.3%, 47.7%, 14.7% and 0.3%, respectively. During a median follow-up of 2.0 years, 759 (8.0%) MACCE events occurred. After multivariable adjustment, MASLD (HR 1.25, 95%CI 1.06-1.48), MetALD (HR 1.31, 95%CI 1.04-1.65) and SLD with other causes (HR 2.81, 95%CI 1.04-7.57) were all significantly associated with higher MACCE risks compared to no SLD. Conclusions A significant proportion of SLD was observed in CCS patients. Patients with various SLD subcategories all had higher risks of recurrent events.

Comparison of open and hybrid endovascular repair for aortic arch: a multi-Centre study of 1052 adult patients.

We aimed to evaluate early and late outcomes by comparing open total arch repair and endovascular arch repair using proximal landing zone analysis in a multicentre cohort. From 2008 to 2019, patients treated surgically for aortic arch disease at six centres were included, excluding cases with type A aortic dissection, additional aortic root replacement, and extensive aortic aneurysm. In all patients and populations with proximal landing zone 0/1 (N = 144) and 2 (N = 187), early and late outcomes were compared using propensity score matching. A total of 1052 patients, including 331 (31%) and 721 (69%) undergoing endovascular arch repair and open total arch repair, respectively, were enrolled. After propensity score match (endovascular arch repair, 295, open total arch repair; 566), no significant difference was observed in in-hospital mortality rate (endovascular arch repair, 6.8%, open total arch repair, 6.2%; p = 0.716). Open total arch repair was associated with a lower risk of all-cause death (log-rank test; p = 0.010, hazard ratio 1.41 [95% confidence interval: 1.17-1.71]). The incidence of aorta-related death was higher in endovascular arch repair (Gray test; p = 0.030, hazard ratio; 1.44 [95% confidence interval; 1.20-1.73]). When compared to endovascular arch repair with proximal landing zone 0/1, open total arch repair was associated with lower risks of all-cause death (log-rank test; p < 0.001, hazard ratio; 2.04 [95% confidence interval; 1.43-2.90]) and aorta-related death (Gray's test; p = 0.002, hazard ratio; 1.67 [95% confidence interval; 1.25-2.24]). There was no difference in the risk of all-cause death (log-rank test; p = 0.961, HR; 0.99 [95% confidence interval; 0.67-1.46]) and aorta-related death (Gray's test; p = 0.55, hazard ratio; 1.31 [95% confidence interval; 1.03-1.67]) between endovascular arch repair with proximal landing zone 2 and open total arch repair. Open total arch repair was considered the first choice based on early and late results; however, endovascular arch repair may be a useful option if the proximal landing zone is limited to zone 2.

Invasive testing leads to significantly altered (surgical) management strategy in coronary anomalies with interarterial course: 3 year interim analysis of MuSCAT

Abstract Introduction Diagnostic work-up of patients with an anomalous aortic origin of a coronary artery (AAOCA) includes an anatomical and functional assessment. The approach to functional evaluation currently varies widely and mainly includes noninvasive assessment. Intracoronary hemodynamic assessment can potentially enhance risk assessment for myocardial ischemia and sudden cardiac death and guide management of AAOCA patients. Hence, this study aims to evaluate invasive detection of ischemia on top of the standard of care diagnostic work-up for interarterial or intraseptal AAOCA and the impact on patient management. We report the first clinical outcomes. Methods In this multicenter prospective cohort study on AAOCA, all consecutive patients of 16 years and older with AAOCA with a newly diagnosed interarterial or intraseptal course in whom diagnostic work-up according to the protocol of the MuSCAT trial was performed between January 2021 and January 2024, were included for analysis. Exclusion comprised incomplete diagnostic evaluation, hemodynamically significant concomitant congenital heart disease or obstructive coronary artery disease in the AAOCA effluence. The work-up included invasive ischemia testing using fractional flow reserve (FFR) and or instantaneous wave-free ratio (iFR)/resting full-cycle ratio (RFR) at baseline and during pharmacological stress using adenosine, adrenaline and dobutamine. Results Fifty-eight patients (50% female, median age at AAOCA diagnosis 51.5 years (IQR 44.0-59.0)) were included, Table 1. The right coronary artery was anomalous in 88%, 93% patients had an interarterial and 69% an intramural course. Non-invasive ischemia detection was positive in 12%, negative in 84% and inconclusive in 4%. Invasive hemodynamic assessment was positive for ischemia in 22%, negative in 74% and inconclusive in 3%. Class of recommendation for surgery based on ESC guidelines was I or IIa in 28% patients and IIb, III or unclassified in 72%. Invasive hemodynamic assessment changed the treatment decision in 24% of the patients; 50% with initially recommended surgical treatment and 14% with initially a conservative treatment adjudication, Figure 1. Median follow-up after initial diagnosis was 20 [IQR 10-28] months and in 56% of all patients who completed 6 months follow-up the initial symptoms alleviated. One (2%) patient underwent a percutaneous re-intervention of the operated AAOCA. Conclusions This national prospective study of invasive hemodynamic assessment in patients with AAOCA showed clinically significant impact on the adjustment of initial management strategy in 24% of the patients. No cardiac death of myocardial infarction in the AAOCA supply area occurred during follow-up. Analysis of the complete follow-up of the MuSCAT trial can further substantiate the role of additional invasive functional imaging in AAOCA.

Incidence, characteristics, and prognostic impact of cancers in patients with atrial fibrillation: a report from the GLORIA-AF registry

Abstract Background Cancers and atrial fibrillation (AF) are all aging-related diseases. Coexistence of the two conditions makes management complex due to increased risk of both thromboembolism and bleeding. Purpose The aim of the present study was to analyze the incidence and prognostic impact of cancers in patients with AF in the GLORIA-AF registry. Methods GLORIA-AF registry is a prospective multi-centered international multi-centered AF cohort studies. We characterized these patients according to the presence or absence of a cancer diagnosis when enrolled. The primary endpoints were all-cause mortality, cardiovascular mortality, and major bleeding; the secondary endpoints were major adverse cardiovascular events (MACEs) including all-cause mortality, stroke, and major bleeding. Results The prevalence of cancers was 9.7%. The mean CHA2DS2-VASc and HAS-BLED scores in cancer patients were higher than in non-cancer patients (mean CHA2DS2-VASc 3.5 vs. 3.2, P&amp;lt;0.001; mean HAS-BLED score 1.6 vs. 1.3, P&amp;lt;0.001). Patients with cancers had higher oral anticoagulant use than non-cancer patients (84.4% vs. 81.0%, P&amp;lt;0.001) and were more likely to receive NOACs (58.4% vs. 54.0%, P&amp;lt;0.001). During a mean follow up period of 3 years, AF patients with cancers had significantly higher all-cause mortality (15.0% vs. 8.3%, P&amp;lt;0.001), major bleeding rate (5.3% vs. 3.1%, P&amp;lt;0.001), the composite of all-cause mortality, stroke, and major bleeding (20.0% vs. 12.0%, P&amp;lt;0.001), and composite of all-cause mortality, thromboembolism, and major bleeding than non-cancer patients (21.0% vs. 12.0%, P&amp;lt;0.001), but nonsignificant differences in cardiovascular mortality (3.6% vs. 3.1%, P=0.2), any stroke, transient ischemic attack, or non-central nervous system embolism (3.2% vs. 2.7%, P=0.1), and OAC discontinuation (29.0% vs. 28%, P=0.2). Among the cancers, hematological cancer was associated the highest risk of all-cause mortality (HR=3.7, 95%CI 2.69-5.0, P&amp;lt;0.001) while respiratory cancer was associated the highest risk of major bleeding (HR=2.62, 95%CI 1.24-5.5, P=0.011). After multivariable adjustment, cancer was independently associated with increased risk of all-cause mortality (HR=1.30, 95%CI 1.05-1.62, P=0.018), composite of all-cause mortality, stroke, and major bleeding (HR=1.32, 95%CI 1.04-1.68, P=0.022), and composite of all-cause mortality, thromboembolism, and major bleeding (HR=1.29, 95%CI 1.04-1.60, P=0.022), but the risk of major bleeding was nonsignificantly different (HR=1.16, 95%CI 0.71-1.87, P=0.6). Conclusions Cancer is a common comorbidity in patients with AF and is independently associated with increased risk of poor outcomes including all-cause mortality and MACEs. However, cancer did not increase the risk of cardiovascular mortality, major bleeding, and discontinuation of OAC. Cancer in patients with AF should receive appropriate treatments for the cancer itself and appropriate OAC, although strategies may vary between different cancers.Distribution of caners in GLORIA-AFKaplan-Meier curves for the outcomes

The gut-microbiome derived phenylacetylglutamine predicts adverse events in patients with acute coronary syndromes

Abstract Background and Introduction The gut microbiota-derived metabolite phenylacetylglutamine (PAG) is associated with incident cardiovascular events(1). Acute coronary syndromes (ACS) present a major health challenge, especially as population ages(2). Data from our group show increased PAG levels during aging in humans. However, the predictive potential of PAG for mortality and major adverse cardiovascular events (MACE) in patients (pts) with ACS is unknown. Purpose Here, we investigated the potential of PAG to predict ischemic and fatal events in pts with acute coronary syndromes (ACS). We also compared the predictive potential of PAG to another relevant gut-microbiota derived metabolite involved in CVD, namely Trimethylaminoxyde, (TMAO), and we evaluated their cumulative risk potential. Methods A total of 1’848 patients were enrolled in Cohort I of the SPUM-ACS study – a multi-center prospective ACS cohort study from Switzerland. Overall survival and incident MACE after 1 year follow-up were analyzed using Kaplan-Meier (KM) estimates and compared by log-rank test after patient stratification into PAG tertiles. Uni- and multivariable Cox-regression models were fit to calculate the hazard ratios for 1-year MACE in a crude model and adjusted model (adjusted for established confounders). Healthy controls served as additional controls. PAG plasma levels were quantified using LC-HRMS. Results The median PAG plasma level in the healthy control group was 1.76µM, whereas for the whole ACS patient population it was 1.92µM (Table 1). Pts in the third PAG tertile had a two times higher MACE rate and a four times higher mortality rate compared to pts in the first PAG tertile (p&amp;lt;0.001). (Table 2). PAG levels were significantly higher in pts who presented with MACE (2.63µM) or died (3.1µM) within the 1-year follow-up compared to the healthy control subjects (p&amp;lt;0.0001) (Figure 1A). Spearman correlation analysis revealed that plasma PAG levels were positively associated with age (r=0.43, p&amp;lt;0.0001), while a negative association with eGFR was observed (r=-0.51, p&amp;lt;0.0001) (Figure 1B). KM estimates indicated that pts in the highest PAG tertile had significantly higher 1-year MACE risk relative to those with low levels (Figure 1C; p&amp;lt;0.001 log rank). Following multivariable adjustment, PAG remained an independent predictor for MACE at 1-year follow-up with a hazard ratio (HR) of 1.8 (95% CI, 1.1–3.2, p=0.048) (Figure 1D). KM estimates of both, high levels of PAG and high levels of TMAO together, indicate that the combination of these two detrimental metabolites leads to an even higher risk of 1-year MACE relative to lower levels (Figure 1E). Conclusion PAG is a novel and independent predictor of adverse outcomes in patients with ACS. This study indicates the role of the gut-microbiome and its metabolites in predicting ischemic and fatal outcomes of pts with established CVD.

Left ventricular volume as a predictor of exercise capacity and functional independence in individuals with preserved ejection fraction

Abstract Background Cardiorespiratory fitness (CRF) is vital for independent living and is a powerful prognostic marker. Increased left ventricular (LV) volume has been linked with high CRF in athletes, but its utility as a diagnostic marker of low CRF across the entire health-disease continuum has yet to be tested. Methods This multi-center international cohort from Australia and Belgium examined the relationship between ventricular size on resting echocardiography and CRF (peakVO2 from cardiopulmonary exercise testing [CPET] or CPET with simultaneous echocardiography) in individuals with preserved LV ejection fraction (≥50%). LV end-diastolic volume (LVEDV) and LVEDV indexed to body surface area (LVEDVi) were tested as predictors of very low CRF (CRF associated with functional disability - peakVO2 &amp;lt; 1100ml or &amp;lt;18 ml/kg/min) and compared against other candidate measures of systolic and diastolic cardiac function that have been associated with heart disease. Thresholds for absolute and indexed LVEDV which best distinguished between lower and higher CRF status were identified. Results 2876 individuals (251 healthy non-athletes, 309 elite endurance athletes, 1969 individuals with unexplained dyspnea, 347 individuals with heart failure with preserved ejection fraction) were included. For the entire cohort, LVEDV had the strongest univariate association with peakVO2 (R2 = 0.45, standardized [std] β 0.67, p&amp;lt; 0.001) and, remained the strongest independent predictor of peakVO2 after adjusting for age, sex and body mass index (std β 0.44, p &amp;lt; 0.001). The relationship between LVEDV and VO2peak differed based on health/disease status (Figure 1). LVEDV demonstrated the greatest diagnostic capability in identifying functional disability (LVEDV AUC 0.72; LVEDVi AUC 0.71, Figure 2), outperforming ejection fraction, diastolic velocities, atrial volumes and pulmonary artery pressure estimates. The probability of achieving a peak VO2 below the threshold required for functional independence was highest for smaller ventricular volumes with LVEDV and LVEDVi of 88ml and 57 ml/m2 proving the optimal cut-points, respectively. Conclusions A small LVEDV is associated with a higher probability of poor exercise capacity, failure to achieve the peak VO2 required for functional independence and is the strongest independent echocardiographic predictor of CRF across the health-disease continuum.Figure 1.Ventricular Size and CRFFigure 2.Predictors of CRF status

Safety of beta-blocker discontinuation in patients after acute coronary syndromes and preserved left ventricular ejection fraction: long-term clinical outcomes from the SPUM-ACS cohort

Abstract Background While beta-blockers have been shown to improve outcomes after acute coronary syndromes (ACS), most trials predate the advent of reperfusion therapy and modern secondary prevention. Recent trial data in the reperfusion era found no all-cause or cardiovascular mortality benefit in patients with a left ventricular ejection fraction (LVEF) &amp;gt;40%, while myocardial infarction and angina were reduced. We hypothesized that, in patients who receive optimal contemporary treatment following ACS and who have an LVEF &amp;gt;40%, beta-blocker discontinuation within 1 year after ACS is safe and non-inferior to beta-blocker continuation in terms of the 5-year incidence of major adverse cardiovascular events (MACE). Purpose We assessed the safety of beta-blocker discontinuation within 12 months following ACS in patients with an LVEF &amp;gt;40% at discharge, compared to continued long-term beta-blocker therapy, with respect to the 5-year incidence of MACE. Methods Data was derived from the Swiss Special Program University Medicine – Inflammation in ACS (SPUM-ACS) cohort (N=3,762), a multicenter prospective cohort of patients hospitalized for invasive management of ACS between 2009-2017. We included patients with an LVEF &amp;gt;40%, beta-blockers at discharge, and who completed the 5-year follow-up. Patients who continued beta-blockers at one year were compared with those who discontinued beta-blockers at any time throughout the first year after ACS using a target trial emulation design. Adjusted hazard ratios (aHR) were obtained with a Cox model using an inverse probability weighting adjustment for baseline characteristics including demographic parameters, comorbidities, and concomitant medication. The primary endpoint was 5-year MACE (cardiovascular death, myocardial infarction, stroke or transient ischemic attack, unplanned coronary revascularization, and hospitalization for unstable angina). Results Of 2,077 patients with an LVEF &amp;gt;40% and beta-blockers at discharge, 1,758 (85%) continued beta-blockers and 319 (15%) had discontinued beta-blocker therapy at one year. The 5-year risk between the discontinuation and continuation group was similar for the primary endpoint (14.5% vs 14.3%, respectively, aHR 1.00, 95%CI 0.73-1.36, p=0.98). All-cause mortality (aHR 1.08, 95%CI, 0.64-1.81, p=0.79) did not differ between both groups. In a subgroup analysis, there was no effect modification by LVEF, but some evidence for a higher risk of primary endpoint with beta-blocker discontinuation in STEMI (aHR 1.50, 95%CI 1.02-2.21) compared with NSTEMI (aHR 0.69, 95%CI 0.40-1.19, P interaction = 0.022). Conclusion Beta-blocker discontinuation within 12 months following ACS in patients with an LVEF &amp;gt;40% was not associated with an increased risk of MACE at 5 years, compared to long-term continuation of beta-blocker therapy. In the absence of a dedicated randomized controlled trial, beta-blocker discontinuation may be safe, especially after NSTEMI.Kaplan-Meier plot: probability of MACE

Association of Vascular endothelial factor D with pulmonary hypertension in heart failure: the PREHOSP-CHF Study

Abstract Background Pulmonary hypertension (PH) complicated with heart failure (HF) is associated with increased morbidity and mortality. Vascular endothelial growth factor D (VEGF-D), one of key regulators of lymphangiogenesis, was reported to be higher in HF patients with pulmonary congestion on chest X-ray. Furthermore, we previously reported that HF patients with high VEGF-D had higher incidence of major adverse cardiovascular events (MACE), defined as cardiovascular death or heart failure hospitalization. Purpose To investigate the association of VEGF-D with pulmonary hypertension in patients with HF. Methods The PREHOSP-CHF study is a multicenter prospective cohort study to determine the predictive value of angiogenesis-related biomarkers in HF. A total of 1,024 patients (mean age 75.5±12.6 years; 58.7% male) admitted to acute decompensated HF were included in the analyses. Serum levels of VEGF-D, as well as N-terminal pro B-type natriuretic peptide (NT-proBNP), high sensitivity cardiac troponin-I (hs-cTnI), high sensitivity C reactive protein (hs-CRP), were measured at the time of discharge. PH was assessed by tricuspid regurgitation velocity (TRV) in echocardiography. Patients were followed-up over two years. Results Data on PH was obtained in 932 patients. Of these, 44 (4.7%) and 223 (23.9%) patients showed PH (TRV&amp;gt;3.4 m/s) and borderline PH (TRV&amp;gt;2.8 m/s), respectively. Patients with PH/borderline PH were significantly older and had lower body mass index. Prevalence of prior HF hospitalization, HF with preserved ejection fraction, atrial fibrillation, anemia, and chronic kidney disease were higher in patients with PH/borderline PH. Levels of NT-proBNP and VEGF-D, but not hs-cTnI or hs-CRP, were higher in patients with PH/borderline PH (Figure). Levels of NT-proBNP and VEGF-D had weak but significant correlation with TRV (NT-proBNP, R2=0.04, P&amp;lt;0.001; VEGF-D, R2=0.05, P&amp;lt;0.001). After adjustment for these factors, VEGF-D levels were significantly correlated with TRV (β, 3.29; SEM, 0.85, P&amp;lt;0.001). During the follow-up, 12 in PH, 34 in borderline PH, and 53 in no PH patients developed MACE. Unadjusted Hazard ratios [95% confidence intervals] for MACE compared to no PH were 2.44 [1.58-3.60] in PH, and 1.62 [1.26-2.05] in borderline PH. When we divided each PH group into two groups based on the median of VEGF-D levels of each group (no PH, 387 pg/ml; borderline PH, 479 pg/ml; PH, 549 pg/ml), patients with high VEGF-D showed significantly higher incidence of MACE in no PH (unadjusted hazard ratio, 1,70; 95% confidence intervals, 1.29-2.26), and tended to show high incidence of MACE in borderline PH group (unadjusted hazard ratio, 1,39; 95% confidence intervals, 0.93-2.09) and PH group (unadjusted hazard ratio, 1,83; 95% confidence intervals, 0.84-4.18). Conclusions VEGF-D levels were independently associated with PH in patients with HF, and might serve as a predictive biomarker for PH, as well as prognostic biomarker for MACE among patients with HF.

Long-term changes in frailty and incident atrial fibrillation: multicenter prospective cohort study

Abstract Background Atrial fibrillation is the most common sustained cardiac arrhythmia and is prevalent among the elderly. Previous findings indicated a higher prevalence of AF in frail adults and frailty prevalent in AF patients. However, the association between dynamic changes of frailty and risk of new-onset AF is unclear. Purpose We aimed to investigate the associations of long-term changes in frailty with incident AF. Its associations with heart failure (HF), coronary heart disease (CHD), and stroke were also evaluated as a secondary aim. Methods Over 50,000 participants from UK Biobank cohort were included, with available frailty index (FI) data and free of AF, HF, CHD or stroke in both baseline and final follow-up assessments. Participants were categorized into nonfrailty, prefrailty and frailty based on their FI scores. Changes of frailty status from baseline to final follow-up assessment included alleviation, maintenance, and aggravation. Thus, transitions of frailty status included 7 categories: nonfrailty maintenance, nonfrailty aggravation (nonfrailty to prefrailty or frailty), prefrailty alleviation (prefrailty to nonfrailty), prefrailty maintenance, prefrailty aggravation (prefrailty to frailty), frailty alleviation (frailty to prefrailty or nonfrailty), and frailty maintenance. FI in baseline and follow-ups are used to calculate the trajectories of frailty (ΔFI). Cox proportional hazard models were used. Results Compared with nonfrailty at baseline, the HRs (95% CI) of AF for prefrailty and frailty were 1.32 (1.29, 1.36) and 1.89 (1.83, 1.96) in the multivariable-adjusted model. During a median of 5.1 years of follow-up from the final assessment, 1729 cases of AF were recorded. Frailty trajectory analysis showed that even a 0.01 point/year increase in ΔFI was associated with 14% (95% CI 1.08-1.20) higher risk of AF, independent of baseline FI and the risk rose to 1.89 (1.45, 2.46) with per 0.05 point/year increase in ΔFI. This association was strengthened in low genetic risk of AF, but sex, age, smoking status, alcohol intake, obesity, hypertension, diabetes and cancer did not materially modify the associations. Moreover, compared with nonfrailty maintenance, sustained frailty had the highest risk of AF (HR 1.95, 1.61-2.36). Alleviation from frailty reduced the risk of AF by 30% (95%CI 0.53-0.94), compared to sustained frailty. These associations were similar in HF and CHD, however, not significant in stroke. Conclusions Middle aged and elderly people, including those with diabetes, obesity and hypertension, may gain substantial benefits in risk of AF, HF and CHD by becoming less frail or maintaining nonfrailty, irrespective of past frailty status and established risk factors, delivering public health implications for the necessity of early identification and timely interventions of frailty in heart health management.