Citations

Abstract Background/Introduction Optimal mean arterial pressure (MAP) in patients with acute myocardial infarction related out-of-hospital cardiac arrest (AMI-OHCA) and cardiogenic shock (AMI-CS) remains unclear. Randomized controlled trials (RCTs) comparing MAP targets have been performed in OHCA patients with presumed cardiac cause, but did not provide answers to the important question what MAP target would be optimal for the AMI-OHCA population. To our knowledge, no RCTs comparing MAP targets in AMI-CS patients have been performed. Purpose This comprehensive systematic review and meta-analysis aimed to evaluate the effect of low- and high-MAP levels on short-term mortality in AMI-OHCA and AMI-CS patients. Methods We conducted a systematic search of MEDLINE (OVID), EMBASE (OVID), CINAHL (Ebsco) and Cochrane CENTRAL databases. Eligible studies reported outcomes for AMI-OHCA or AMI-CS patients for at least two groups of different average MAP levels. Both RCTs and observational studies were eligible to ensure comprehensive data collection. Authors were proactively contacted for supplementary AMI data. Random-effects models were used to pool data. Results Of 7,728 screened studies, 57 were assessed for eligibility, and 11 were included in the final analysis (4 RCTs and 7 observational studies), encompassing 3,846 patients. The primary analysis included 1,251 AMI-OHCA patients. In the AMI-OHCA patients, no significant difference in short-term mortality was observed between low- and high-MAP groups in RCT (34.9% vs. 39.4%, RR 0.88, 95%-CI 0.70-1.10), observational-, and combined data. As only one of the 11 included studies reported on separate AMI-CS data, no meta-analyses of solely AMI-CS patients could be performed. Conclusions Our meta-analysis showed no significant difference in short-term mortality between low- and high-MAP levels in AMI-OHCA patients. Only one study in selected AMI-CS patients without OHCA patients was available. This highlights the importance of identifying tailored MAP strategies in both AMI-OHCA and AMI-CS patients.Flow chart of the selection of studies Short term mortality – AMI-OHCA patients

Abstract Background The impact of treatment for tricuspid regurgitation (TR) across different levels of left ventricular ejection fraction (LVEF) remains uncertain. Purpose This study aimed to compare the outcomes of surgical and transcatheter tricuspid valve interventions (TTVI) to conservative (medical) management across all LVEF categories. Methods Patients with severe isolated TR from the TRIGISTRY, a multicenter international registry, were categorized based on LVEF (preserved EF-pEF:≥50%, mildly reduced EF-mrEF:41–49%, and reduced EF-rEF:≤40%). We assessed the impact of treatment modality and procedural success, defined as residual TR ≤mild-to-moderate, on two-year survival within each LVEF category. Results Among 2,384 patients, 1,383 had pEF, 400 had mrEF, and 601 had rEF. Compared to conservative management, surgery (P<0.0005) and TTVI (P<0.0001) were associated with a survival benefit in patients with pEF. No significant survival advantage was observed in patients with mrEF (P=0.28 for both), nor in those with rEF (P=0.76 and P=0.22 respectively). Similar results were obtained when surgical and transcatheter interventions were grouped together (P<0.0001, P=0.17 and P=0.29 in patients with pEF, mrEF and rEF respectively). Patients with significant residual TR after TTVI exhibited a trend toward worse survival compared to those managed conservatively across all LVEF categories (P=0.47, P=0.33, and P=0.008 respectively)(Figure 1). Conclusion Tricuspid valve intervention, whether surgical or transcatheter-based, was associated with improved survival in patients with preserved LVEF but not in those with mildly reduced or reduced LVEF. Residual TR remained a significant prognostic factor across the entire LVEF spectrum. These findings highlight the need for careful patient selection when considering tricuspid interventions in individuals with reduced LVEF.Figure 1

Abstract Background While tricuspid regurgitation (TR) is predominantly functional, it can arise from various cardiac conditions. This study aimed to evaluate whether the benefits of tricuspid valve intervention, compared to conservative management, differ based on the underlying etiology. Methods In the TRIGISTRY international cohort, which includes consecutive patients with severe isolated functional TR across 33 centers in 10 countries, we compared mortality rates at 2 years between patients who underwent a tricuspid valve intervention (surgical or transcatheter) versus conservative management according to TR etiology. Patients were classified into three groups: (1) Isolated TR (ITR), defined as left ventricular ejection fraction (LVEF) >60%, systolic pulmonary artery pressure (sPAP) <50 mmHg, and no prior left-heart intervention (LHI); (2) LHI-TR, comprising patients with a history of LHI; and (3) Undetermined TR (UTR), which included those who did not meet the criteria for ITR or LHI, as well as those with missing sPAP data. Given previous findings indicating that intervention provided no survival benefit for patients with a high TRI-SCORE, the present analysis was restricted to individuals with low to intermediate TRI-SCORE (≤5). Survival outcomes between groups were compared using restricted mean survival time (RMST). Results A total of 1,552 patients (72±13 years; 56% female) with severe functional TR and a low (48%) or intermediate (52%) TRI-SCORE were included. Of these, 772 (50%) underwent an intervention, while 780 (50%) were conservatively managed. TR was classified as ITR in 201 patients (13%), LHI in 395 (25%), and UTR in 956 (62%). Overall, patients with ITR exhibited the lowest comorbidity burden, whereas those with UTR had the highest. After adjusting for comorbidities and TRI-SCORE, a survival benefit of a tricuspid valve intervention was observed in patients with ITR (survival estimate: 0.17, 95% CI [0.009, 0.32], P=0.039) and, to a lesser extent, in patients with UTR (survival estimate: 0.09, 95% CI [0.0, 0.184], P=0.048), but not in those with prior LHI (survival estimate: 0.06, 95% CI [-0.08, 0.2], P=0.4). Similar results were found when excluding patients with moderate or greater residual TR after intervention. Conclusion In TRIGISTRY, patients with ITR appeared to derive the greatest benefit from tricuspid valve intervention, followed to a lesser extent by those with UTR, while no benefit was observed in patients with prior LHI. However, the potential influence of unaccounted confounders cannot be excluded, and further studies are needed to better identify patients’ subsets that may derive the most benefit from a tricuspid valve intervention.

Background and Aims: Cholangiocarcinoma (CCA) is a rare but aggressive malignancy with poorly understood genetic susceptibility. To date, genome-wide association studies (GWAS) investigating germline variants associated with CCA risk remain limited. We aimed to identify genetic risk loci for CCA and its clinical subtypes through comprehensive GWAS and post-GWAS analyses. Approach and Results: We conducted a GWAS of 2366 CCA cases and 11,750 controls of European ancestry. Genome-wide significant loci ( p <5×10 −8 ) were identified and further examined through fine-mapping, functional annotation, and HLA imputation. Subgroup analyses were conducted by CCA subtypes and primary sclerosing cholangitis (PSC) status. Cross-trait linkage disequilibrium score regression and Mendelian randomization were employed to investigate the shared genetic architecture and potential causal relationships with a diverse range of traits. We identified 1 new genome-wide significant variant, rs535777 (OR=1.44), near HLA-DRB1/DQA1 associated with CCA, and 2 variants associated with extrahepatic CCA: rs116224263 (OR=0.17) in LINC02506 at 4p15.1 and rs6914950 (OR=1.63) near HLA-DRB1/DQB1 . Stratified analyses revealed rs2395184 (OR=3.51) near HLA-DRA/DRB5 associated with PSC-related CCA, and rs142674434 (OR=2.98) in THSD7A at 7p21.3 associated with non-PSC-related CCA. HLA imputation uncovered new amino acid residues associated with disease risk. Cross-trait analyses identified shared genetic signals between CCA and anthropometric, lipidemic, lifestyle, and medical traits. Mendelian randomization supported putative causal associations for 12 traits with CCA or its subtypes. Conclusions: Our large-scale GWAS highlights new genetic variants and HLA-linked mechanisms underlying CCA susceptibility. Integrating multi-step post-GWAS approaches enhances understanding of CCA pathogenesis and may facilitate the development of risk biomarkers for early detection and precision prevention strategies.

Abstract Background While type 2 diabetes (T2DM) is a known risk factor for aortic valve calcification (AVC) and aortic stenosis (AS), the specific mechanisms remain unclear. The aim of this study was to determine early factors associated with AVC in patients with T2DM. Methods This cross-sectional study is a pre-specified substudy of an ongoing multicenter randomized controlled trial, the STENO INTEN-CT trial (Screening and Intervention for Subclinical Coronary Artery Disease in Patients With Type 2 Diabetes). Eligibility criteria are patients with diagnosed T2DM without prior ischemic heart disease, and age between 55-69 years (male) and 60-74 years (female). All patients underwent a non-contrast cardiac computed tomography scan and AVC was measured in Agatston units. Results Of the 3635 patients included in this study, nearly half (n = 1694) demonstrated an AVC &gt; 0 (n=1502 with 0 &lt; AVC &lt; 300 and n = 192 with AVC ≥ 300). With increasing AVC, patients were elder, predominantly males, and had significantly more comorbidities (obesity, hypertension, chronic obstructive pulmonary disease, and kidney dysfunction). Patients with higher AVC were more likely to be treated with statins (AVC = 0: n = 1509 (78%), 0 &lt; AVC &lt; 300: n = 1217 (81%), AVC ≥ 300: n = 163 (85%), p = 0.009). Higher body mass index (OR: 1.03 (1.02-1.04), p &lt; 0.001), statin use (OR: 1.49 (1.24-1.80), p &lt;0.001), low-density lipoprotein (OR: 1.24 (1.12 - 1.37), p &lt; 0.001), and kidney dysfunction, measured as urine albumine-creatinine ratio (OR: 1.00 (1.00-1.00), p &lt;0.001), were independently associated with increasing AVC (Figure 1). However, T2DM severity, measured as the duration of T2DM, HbA1c levels, and the number of antidiabetic drugs used, was not associated with increasing AVC severity (Figure 1+2). Conclusion AVC is highly prevalent, affecting nearly half of patients with T2DM. However, early factors driving AVC are not associated with T2DM severity, but rather to diabetes-related comorbidities and complications.

Abstract Background Measurement of cardiac troponin (cTn) using high-sensitivity assays is recommended for the diagnosis of myocardial infarction. We determined sex-specific and uniform 99th percentile upper reference limits (URLs) using the new Elecsys® Troponin T high-sensitivity Gen 6 assay in a global, healthy reference range cohort. Methods Lithium-heparin plasma and serum samples were prospectively collected from apparently healthy individuals aged ≥20 years across 34 global sites in the United States, Europe, China, and Japan. cTnT was measured using the Troponin T high-sensitivity Gen 6 assay on the Cobas® e 801 analyzer. Exclusion criteria were defined according to the 2022 IFCC guidance. Uniform and sex-specific 99th percentile URLs and nonparametric 95% CIs were determined in plasma and serum separately and combined. Results The final study population comprised 4147 participants (52.5% female) with a median (25th–75th percentiles) age of 48.0 (33.0–59.0) years; 45.8%, 47.9%, 5.2%, and 1.1% were White, Asian, Black, and other/unknown, respectively. For sample matrices combined (n = 8294), 81.0% and 99.2% of cTnT values were above the limit of detection in females and males, respectively. Sex-specific 99th percentile URLs (95% CI) were 18 (16–23) ng/L for females and 32 (28–35) ng/L for males; the uniform 99th percentile URL was 27 (24–31) ng/L. URLs were comparable in plasma and serum samples. Conclusions This study determined sex-specific and uniform 99th percentile URLs for the Troponin T high-sensitivity Gen 6 assay that were comparable irrespective of the matrix used in a large, global, healthy reference population.

BACKGROUND AND OBJECTIVES: Unruptured intracranial aneurysms (UIAs) are increasingly detected and require careful management to prevent rupture. No externally validated score currently predicts procedural risk to guide treatment decisions. We developed and validated 2 predictive scores for complications after endovascular treatment (EVT) or neurosurgical treatment (NT) of UIA using routinely collected clinical and aneurysmal features. METHODS: We conducted a multicenter retrospective study including patients with UIA treated with EVT or NT across 15 neurovascular centers (2014-2024). Predictive models were built using multivariable logistic regression, with variables derived from Delphi consensus. The primary outcome was a composite safety end point: new neurological deficits, modified Rankin Scale (mRS) worsening (≥1 point or mRS 2-5 within 30 days), or procedural death. Internal validation used bootstrapping, and external validation was performed temporally and institutionally. Model performance was assessed using area under the receiver operating characteristic curve (AUROC) and calibration. Final scores, named Morbidity and Mortality Associated Risk in the Treatment of UIAs (MARTA)-EVT and MARTA-NT, were compared with existing models identified through systematic review. RESULTS: Among 2647 patients (1907 EVT and 740 NT), procedural complications occurred in 6.3% (EVT) and 12.8% (NT). Independent predictors included age, baseline mRS, aneurysm location, size, morphology, and procedural factors. MARTA-EVT (AUROC = 0.68, 95% CI = 0.57-0.78) and MARTA-NT (AUROC = 0.65, 95% CI = 0.54-0.77) showed moderate discrimination and good calibration. MARTA-EVT outperformed existing models; MARTA-NT performed similarly to SAFETEA. Predictive models are available open-source: https://martascoreapp.shinyapps.io/martascoreapp/. CONCLUSION: MARTA-EVT and MARTA-NT are validated tools for predicting procedural risks in UIA treatment and may support patient counseling and clinical decision making.

378 Background: RATIONALE-305 (NCT03777657) enrolled the highest number of pts with PM among similar trials and stratified pts with advanced GC/GEJC by presence of PM. We used statistical modeling to evaluate the impact of varying PM levels on outcomes with TIS+CT. Methods: We randomized adults with GC/GEJC (1:1) to TIS or placebo (PBO) + CT. Primary endpoints: OS in intent-to-treat (ITT) population and pts with programmed death-ligand 1 (PD-L1) Tumor Area Positivity (TAP) score ≥5%. We weighted pts using the method of moments to match a hypothetical population to ITT, with the same distribution of sex, primary tumor location, PD-L1 (TAP score <5% vs ≥5%), number of metastatic sites (0-2 vs 3+), and liver metastasis. PM representation was set from 20% to 45%. Weighted OS, PFS, and objective response rate (ORR) were estimated. Results: Of 997 pts enrolled, 434 (43.5%) had PM. Among pts with PD-L1 TAP scores ≥5% (54.8%), 39.7% had PM, and among pts with scores ≥1% (88.9%), 43.6% had PM (data cutoff Feb 28, 2024). Fewer pts with (+) PM had PD-L1 high tumors (TAP score ≥5%: 50.0%) and more had primary stomach tumors (86.6%) compared to those without (-) PM (58.4% and 75.5%). TIS+CT improved OS, PFS, and ORR in ITT and in pts +/- PM vs PBO+CT (Table). Across 20%–45% PM, TIS+CT showed consistent benefit, with stable HRs for OS and PFS (20% and 45% shown). TIS+CT showed survival benefits in pts with PM and PD-L1 TAP score ≥5% (OS: HR=0.71; PFS: HR=0.65) and ≥1% (OS: HR=0.79; PFS: HR=0.79) vs PBO+CT. ORR was higher with TIS+CT vs PBO+CT in pts + PM and PD-L1 TAP scores ≥5% (47.3% vs 30.8%) and ≥1% (44.2% vs 33.2%). Conclusions: Our analysis showed that lowering PM representation marginally improved OS and ORR, underscoring the poor prognosis of peritoneal disease. In RATIONALE-305, TIS+CT provides clinically meaningful response and survival benefits irrespective of PM, with higher responses in PD-L1+ GC/GEJC. Clinical trial information: NCT03777657 . Arm(95% CI) ITT + PM - PM 20%+ PM 45%+ PM OS, months TIS+CT 15.0 (13.6, 16.5) 12.3 (10.6, 14.3) 17.3 (15.0, 20.3) 15.4 (13.9, 18.0) 15.0 (13.5, 16.5) PBO+CT 12.9 (12.1, 14.1) 11.8 (10.5, 13.0) 14.0 (12.6, 16.0) 13.1 (12.3, 14.5) 12.8 (12.1, 14.1) HR 0.79 (0.69, 0.91) 0.78 (0.64, 0.96) 0.79 (0.65, 0.95) 0.81 (0.69, 0.95) 0.79 (0.69, 0.90) PFS, months TIS+CT 6.9 (5.7, 7.2) 5.8 (5.6, 7.3) 7.0 (5.7, 8.4) 6.9 (5.7, 7.3) 6.9 (5.7, 7.2) PBO+CT 6.2 (5.6, 6.9) 5.7 (5.3, 6.9) 6.9 (5.7, 7.1) 6.5 (5.6, 7.0) 6.2 (5.6, 6.9) HR 0.79 (0.68, 0.91) 0.80 (0.64, 0.98) 0.77 (0.64, 0.94) 0.79 (0.67, 0.94) 0.79 (0.69, 0.91) ORR, % TIS+CT 47.3 (42.9, 51.8) 43.6 (37.0, 50.5) 50.2 (44.2, 56.2) 48.0(42.9, 53.1) 47.3 (42.8, 51.8) PBO+CT 40.5 (36.2, 45.0) 32.2 (26.0, 39.0) 46.8 (40.9, 52.8) 43.1(38.1, 48.3) 40.3(36.0, 44.8) ORR difference, % 6.8 (0.6, 12.9) 11.4 (2.3, 20.3) 3.4 (-4.9, 11.6) 4.9 (-2.2, 11.9) 6.9 (0.8, 13.0)

Abstract Background Sex, education and race/ethnicity are all associated with risk of Alzheimer's disease dementia. Here, we assess the effects of self‐reported sex, educational attainment and race/ethnicity on amyloid‐positivity, and tau‐PET‐positivity in 12,048 (7,394 cognitively unimpaired [CU], 2,177 MCI, and 2,477 dementia) individuals from 42 cohorts worldwide. Method Logistic generalized estimating equations were used to estimate frequency of amyloid‐positivity (using cohort‐specific thresholds for amyloid‐PET [84%] or CSF) and tau‐PET‐positivity (cohort‐specific thresholds of 2SD above mean temporal uptake in amyloid‐negative controls). We assessed: i) sex and APOEε4 ( N = 10,098) associations, to complement earlier findings of a higher frequency of tau‐positivity in females, ii) effects of lower/higher education ( N = 10,970; cohort‐specific median‐split), and iii) effects of race/ethnicity (non‐Hispanic White [hereafter: White], N = 4880; Asian, N = 116; Black or African‐American [hereafter: Black], N = 353; Hispanic, N = 356, only from Northern‐American cohorts). Outcomes were frequency of amyloid‐positivity in CU individuals only, and tau‐PET‐positivity in both amyloid‐positive (AB+) CU and cognitively impaired (CI, i.e. MCI and dementia) individuals. Interaction effects on the relationship between age and amyloid/tau‐positivity were assessed and only retained in the models when significant. Result Female sex was associated with an APOEε4 ‐independent increased frequency of amyloid‐positivity (β=0.51[0.22], p = 0.02) in CU and increase of tau‐positivity in both AB+CU (β=0.27[0.08]) and AB+CI (β=0.37[0.08], both p <0.01). Remarkably, tau‐positivity frequencies of female APOEε4 non‐carriers were equivalent to male APOEε4 carriers in AB+CI (Figure 1). No significant sex* APOE interactions were observed. In CU, higher education was associated with lower amyloid‐positivity frequency (β=‐0.12[0.05], p = 0.02). In contrast, among AB+CU, there was an age*education interaction effect that indicated more pronounced age effects on tau‐positivity in individuals with higher education (age*education:β interaction =0.03[0.01], p <0.01). There were no education effects in AB+CI (Figure 2). In CU, an age*race/ethnicity interaction effect was observed across all non‐White groups compared to White (Hispanic:β interaction =‐0.05[0.01], p <0.01; Black:‐0.04[0.01], p <0.01; Asian:‐0.02[0.01], p = 0.04). This suggests that the impact of age on amyloid‐positivity was less pronounced in non‐White groups. Furthermore, in AB+CI, Hispanic ethnicity was related to higher tau‐positivity frequency than White (β=0.51[0.22], p = 0.02; Figure 3). Conclusion In this multi‐center initiative comprised of clinical and community‐based cohorts, we observed that self‐reported sex, educational attainment and race/ethnicity were related to positivity‐frequencies of Alzheimer's disease pathology.

Abstract INTRODUCTION Tau species lacking truncation of the N‐terminal region, including plasma N‐terminal tau fragment 1 (NT1), have been previously associated with cognitive decline, neurodegeneration, and tau pathology in late‐onset sporadic Alzheimer's disease (AD). METHODS Here, we examined cross‐sectional and longitudinal plasma NT1 as a possible predictor of cognitive, clinical, and core AD biomarker trajectories in autosomal dominant AD (ADAD). RESULTS NT1 levels in ADAD mutation carriers (MC; n = 132) increased across the disease continuum, compared to non‐carriers (NC; n = 75), becoming elevated about a decade prior to estimated symptom onset. Cross‐sectional and longitudinal NT1 levels in MC were associated with clinical, cognitive, and biomarker changes. NT1 increases continued in symptomatic phases of disease, a distinct trajectory from that seen with CSF p‐tau217 and other phospho‐tau species. DISCUSSION Together, our results suggest that plasma NT1—alone or combined with other tau measures—may be useful in studying AD‐related clinical, cognitive, and biomarker outcomes. Highlights Leveraging a deeply phenotyped cohort of individuals carrying a pathogenic variant for autosomal dominant Alzheimer's disease (ADAD) and their non‐carrier family members, our results suggest that plasma N‐terminal tau fragment 1 (NT1) levels mirrored changes in clinical, cognitive, and neurodegenerative measures in ADAD, particularly in late asymptomatic and early symptomatic phases of disease. NT1 levels correlated with cerebrospinal fluid (CSF) measures of tau pathology but less so with CSF or imaging measures of β‐amyloid pathology. Together with previous supportive findings in preclinical and symptomatic sporadic AD, these results suggest that plasma NT1—alone or combined with other tau measures—may be useful in studying AD‐related tau pathology and neurodegeneration across a wide spectrum of disease.