Occurrence Of Death Research Articles

Evaluation of Reactive Oxygen Species Scavenging of Polydopamine with Different Nanostructures.

Reactive oxygen species (ROS) play an important role in cellular metabolism and many oxidative stress-related diseases, while excessive accumulation of ROS will lead to genetic changes in cells and promote the occurrence of inflammatory diseases or cell death. Nature-inspired polydopamine (PDA) with tailored nanostructures emerges as an ROS scavenger and is considered as an effective approach to inflammation-related diseases. However, the effects of nanoparticle structure on PDA scavenging efficacy and efficiency remain uncovered. In this work, three typical PDA nanoparticles including solid PDA, mesoporous PDA, and hollow PDA are synthesized, and of which physiochemical properties are characterized. Furthermore, their ROS scavenging performance is investigated by in vitro evaluation of radical removal. Among the three nanoparticles, mesoporous PDA is demonstrated to have the highest scavenging capability, mainly due to its specific surface area. Finally, the study on three in vivo inflammation models is constructed. The results confirm that mesoporous PDA is the most potent scavenger of ROS and more effective in reducing reperfusion injury, improving renal function, and preventing periodontitis progression, respectively. Together with the good biosafety and biocompatibility profiles, PDA nanoparticles, mesoporous PDA in particular, can be a promising avenue of ROS scavenging in fight against the inflammatory diseases.

Asbestos-related cancer in naval personnel: findings from participants in the British nuclear tests 1952–1967

Asbestos-containing materials (ACM) were present in British and Australian naval vessels throughout the twentieth century. The aim of this study was to identify and quantify the incidence of cancer in naval personnel from onboard asbestos exposure. Subjects were four cohorts of subjects who had served in the armed forces of the United Kingdom and Australia in the 1950s and 1960s. All cohorts had previously been studied, three of them in relation to radiation exposures from British nuclear testing. Comparisons of SIRs between services were made to identify cancers attributable to asbestos exposure. Excess mesotheliomas were found in naval personnel in all cohorts. In all but one cohort the lung cancer incidence was highest in navy personnel. Comparison of other smoking-related conditions indicated that the excess in navy personnel was not smoking-related. The relatively high SIRs for mesothelioma and the occurrence of deaths from asbestosis were indicative of high levels of asbestos exposure, with an expectation of cases of asbestos-related lung cancer. The findings are consistent with the occurrence of significant excesses of mesotheliomas. In addition, notwithstanding some inconsistencies in the results between the cohorts, we estimated that approximately 27% of lung cancers in Australian seamen and 12% in British seamen were related to onboard asbestos exposure.

Fully automated assessment of global longitudinal strain by machine learning predicts death in patients undergoing stress CMR

Abstract Background Several studies described the independent prognostic value of left ventricular global longitudinal strain (GLS) using cardiovascular magnetic resonance (CMR) to predict death and cardiovascular events. While routine GLS evaluation is a time consuming and partially operator-dependent process, the potential interest of GLS using a fully automated method has not yet been established. Purpose To assess the feasibility and prognostic value of GLS to predict all-cause death using a fully automated machine-learning algorithm without human correction in consecutive patients referred for stress CMR. Methods Between 2016 and 2018, all consecutive patients referred for stress CMR were included and followed for the occurrence of all-cause death. A fully automated machine learning algorithm was trained and validated on unseen CMR studies (MAGNETOM Aera and Skyra) to assess the GLS from long-axis cine images acquired at rest. The algorithm combines multiple deep learning networks for detection and segmentation with an active contours approach. Cox regressions were performed to determine the prognostic value of GLS. Results In a retrospective study of 9,883 consecutive patients who underwent stress CMR between 2016 and 2018, automated GLS was successfully computed in 9,638 (97.5%) patients (67% male, mean age 66±12 years). A total of 510 (5.3%) deaths were observed during a median follow-up period of 4.5 years (interquartile range: 3.7-5.2). GLS, the presence of inducible ischemia and late gadolinium enhancement (LGE) were significantly associated with the occurrence of death (hazard ratio, HR: 1.22 [95% CI, 1.17-1.26]; HR: 2.23 [95% CI, 1.61-3.10]; and HR: 2.04 [95% CI, 1.41-2.95], respectively, all p<0.001). After adjustment for traditional risk factors, inducible ischemia and LGE, GLS was an independent predictor of a higher incidence of death (adjusted HR: 1.14 [95% CI, 1.08-1.20]). Automated GLS showed an incremental prognostic value to predict death compared to traditional risk factors, inducible ischemia and LGE (C-statistic improvement: 0.05; NRI=0.146; IDI=0.244; all p<0.001). Conclusions Fully automated GLS measured at rest has an incremental prognostic value to predict all-cause death above traditional risk factors, and other stress CMR parameters. This finding suggests that unsupervised GLS measurements are accurate and allow improved risk stratification.

Left atrioventricular coupling index assessed using cardiac CT as a prognostic marker of cardiovascular death

Abstract Background Although the left atrioventricular coupling index (LACI) measured by cardiovascular magnetic resonance (CMR) is a strong predictor of cardiovascular events, the availability to CMR remains limited in clinical routine. Therefore, it would be useful to validate LACI assessment using other imaging methods such as computed tomography (CT). However, the feasibility of LACI measurement using cardiac CT and its prognostic value are not established. Purpose We aimed to investigate the prognostic value of the LACI assessed by cardiac CT, to predict the occurrence of cardiovascular death in consecutive patients without known CVD referred for coronary CT angiography (CCTA). Methods Between 2010 and 2020, we conducted a single-center study with all consecutive patients without known CVD referred for CCTA. LACI was defined as the ratio of LA to LV end-diastolic volumes. The primary outcome was cardiovascular death. Cox regressions were used to evaluate the association of LACI with the primary outcome after adjustment for traditional risk factors and CCTA findings. Results In 1,444 patients (70±12 years, 43% men), 92 (6.4%) patients experienced all-cause death, including 67 (4.3%) patients with cardiovascular death after a median (IQR) follow-up of 6.8 (5.9-9.1) years. After adjustment for risk factors and CCTA findings, LACI was positively associated with the occurrence of cardiovascular death (adjusted hazard ratio [HR], 1.07 [95% CI, 1.05-1.09] per 1% increment, p<0.001), and all-cause death (adjusted HR, 1.05 [95% CI, 1.03-1.07] per 1% increment, p<0.001). After adjustment, a LACI ≥25% showed the best improvement in model discrimination and reclassification above traditional risk factors and CCTA findings (C-statistic improvement: 0.27; NRI=0.826; IDI=0.209, all p<0.001; LR-test p<0.001). Conclusions LACI measured by CCTA is independently associated with cardiovascular death and all-cause death in patients without known CVD referred for CCTA, with an incremental prognostic value over traditional risk factors and CCTA findings.LACI measurement using CCTASurvival curves stratified by LACI value

Safety and incremental prognostic value of stress CMR in patients with known chronic kidney disease

Abstract Background Cardiovascular disease (CVD) is the main cause of mortality in patients with chronic kidney disease (CKD). Although several studies have demonstrated the consistently high prognostic value of stress cardiovascular magnetic resonance (CMR), its prognostic value in patients with CKD is not well established. We aimed to assess the safety and the incremental prognostic value of vasodilator stress perfusion CMR in consecutive symptomatic patients with known CKD. Methods Between 2008 and 2021, we conducted a bi-center longitudinal study with all consecutive symptomatic patients with known CKD, defined by estimated glomerular filtration rate (eGFR) between 30 and 60 ml/min/1.73 m2, referred for vasodilator stress CMR. All patients with eGFR <30 ml/min/1.73 m² (n=62) were excluded due the risk of nephrogenic systemic fibrosis. All patients were followed for the occurrence of major adverse cardiovascular events (MACE) defined as cardiac death or recurrent nonfatal myocardial infarction (MI). Cox regressions were used to determine the prognostic value of stress CMR parameters. Results Of 825 patients with known CKD (71.4±8.8 years, 70% men), 769 (93%) completed the CMR protocol, and among those 702 (91%) completed the follow-up (median follow-up 6.4 (4.0–8.2) years). Stress CMR was well tolerated without occurrence of death or severe adverse event related to the injection of gadolinium or nephrogenic systemic fibrosis case. The presence of inducible ischemia was associated with the occurrence of MACE (hazard ratio [HR] 12.50; 95% confidence interval [CI]: 7.50–20.8; p<0.001). In multivariable analysis, ischemia and late gadolinium enhancement were independent predictors of MACE (HR 15.5; 95% CI: 7.72 to 30.9; and HR:4.67 [95%CI: 2.83-7.68]; respectively, both p<0.001). After adjustment, stress CMR findings showed the best improvement in model discrimination and reclassification above traditional risk factors (C-statistic improvement: 0.13; NRI=0.477; IDI=0.049). Conclusions In patients with known CKD, stress CMR is safe and its findings have an incremental prognostic value to predict MACE over traditional risk factors.Cumulative rates of MACECompeting risk analysis

Non-invasive measurement of global myocardial work to predict all-cause death and heart failure hospitalization in non-ischemic cardiomyopathy

Abstract Background Global myocardial work (GMW) can be non-invasively calculated using a dedicated software using global longitudinal strain (GLS) and blood pressure. The prognostic value of GMW in patients with non-ischemic cardiomyopathy (NICM) has not yet been demonstrated. Purpose To stablish the prognostic significance of GMW in NICM. Methods Patients with NICM with an available echocardiogram between 2015 and 2019 and left ventricular ejection fraction (LVEF) <50% were retrospectively included. A dedicated software was used to analyze GMW, global constructive work (GCW), global wasted work (GWW) and global work efficiency (GWE). All quantitative variables were modelled as a spline with three knots to account for non-linear associations. Patients were followed up until the occurrence of death, heart failure hospitalization or lost to follow-up. The primary endpoint was a composite of all-cause death of heart failure hospitalization (HFH). Results A total of 524 patients with NICM in whom GMW analysis was feasible were included in the study. Median LVEF was 35 (IQR 27 – 42), and median GMW was 968 (IQR 670 – 1282). There were no significant differences in clinical characteristics between patients with GMW above or below median, except for higher rates of HFH during the previous year in patients with lower GMW. Patients with lower GMW displayed lower LVEF, greater LV dilatation, worse GLS, lower TAPSE and a higher E/e’ ratio (Table 1). GMW and GCW were significantly collinear with GLS (Pearson’s r = -0.85 and -0.83 respectively, p<0.001), GWE was moderately collinear (Pearson’s r = -0.64, p<0.001) whereas GWW was not (Pearson’s r = 0.05, p = 0.23). During a median follow-up of 4.8 years, 164 (31.3%) patients presented the primary endpoint. After adjusting for age, LVEF, end-diastolic volume and TAPSE, GMW showed a significant, non-linear association with the primary endpoint (Figure 1), at the expense of both death and HFH when separately analyzed. Risk progressively increased with a GMW below 2500 mmHg% and plateaued at 1000 mmHg%. Only GCW retained an association with the primary outcome like the one observed with GMW, whereas GWW and GWE did not. Adding GMW to the model led to an improved risk discrimination (AUC increased from 0.66 to 0.69, p = 0.043). Conclusions Global myocardial work and GCW are new independent echocardiographic predictors of all-cause death and HFH in NICM, with higher rates of the outcome at lower GMW and GCW values, whereas GWW and GWE were not associated with event rates in NICM.

Lower dose direct oral anticoagulation and warfarin in atrial fibrillation. Ischemic stroke, intracranial hemorrhage and mortality in a nationwide registry study

Abstract Background and aims Direct oral anticoagulants (DOACs) have replaced Vitamin-K antagonists as the primary choice of oral anticoagulation (OAC) in atrial fibrillation (AF). However, after several years of experience with DOACs, no studies have been made comparing the efficacy and safety of reduced dose DOACs and warfarin when the quality of warfarin treatment (time in the therapeutic range, TTR) information is available. Methods The Finnish AntiCoagulation in Atrial Fibrillation (FinACAF) is a nationwide study of AF patients combining data from several Finnish healthcare registers. We included all new-onset AF patients from 2011 to 2018 in Finland with purchases of either reduced dose DOAC or warfarin with eligible laboratory data. For patients on warfarin, we calculated TTR percentages and divided patients into TTR quartiles. Occurrence of ischemic stroke (IS), intracranial haemorrhage (ICH), or death during OAC use were recorded as outcomes during a maximum follow-up of 730 days. Crude and weighted rates of IS, ICH and mortality are provided. To minimize confounding by baseline characteristics and concomitant medications, an inverse probability of treatment weighted analysis was applied. Results A total of 52,022 new-onset AF patients with OAC therapy (46.1% male, mean age 75.7 years, 43 548 on warfarin) were followed for 56 382 patient-years (py). The rate of IS among patients was 1.63/100 py for dabigatran (n=2 672), 1.64/100 py for apixaban (n=3 936), 1.49 /100 py for rivaroxaban (n=1 866). For patients with warfarin, the rates of IS in TTR quartiles were 3.45, 1.79, 1.18 and 0.74/100 py from the lowest (mean TTR 32%) to the highest TTR quartile (mean TTR 90%). The weighted rates of IS were 1.34, 0.96 and 1.25/100 py for dabigatran, apixaban and rivaroxaban, and for warfarin from the lowest to the highest quartile: 3.70, 1.87, 1.21 and 0.97/100 py. The rates of ICH were 0.68, 1.09 and 1.06/100 py for dabigatran, apixaban and rivaroxaban, and for warfarin from the lowest to the highest quartile: 3.60, 0.99, 0.51 and 0.32/100 py. The weighted rates of ICH were 0.70, 0.70 and 0.90/100 py for dabigatran, apixaban and rivaroxaban, and for warfarin from the lowest to the highest quartile: 3.80, 1.03, 0.54, 0.34 and 0.97/100 py. For mortality, raw incidences rates were 4.31, 11.40, and 8.11/100 py for for dabigatran, apixaban and rivaroxaban, and for warfarin from the lowest to the highest quartile: 16.45, 5.33, 2.31, and 1.53/100 py. The weighted rates were 3.97, 7.97, and 6.78, for dabigatran, apixaban and rivaroxaban, and for warfarin from the lowest to the highest quartile: 18.08, 5.86, 2.58, and 1.73/100 py. Figures portray cumulative IS incidence and mortality. Conclusion The incidence rates of all three outcomes were highest among patients on warfarin in the lowest TTR quartiles. For reduced dose DOAC patients, weighted IS rates were highest for those on dabigatran, ICH rates for those on rivaroxaban, and mortality rates for those on apixaban.Cumulative Incidence of Ischemic StrokeCumulative mortality

Layer-specific circumferential strain using fast strain-encoded cardiac magnetic resonance imaging in acute myocardial injury - a prospective study of diagnostic and prognostic accuracy

Abstract Background In patients presenting acutely with chest pain or shortness of breath, an acute myocardial injury diagnosed through modern troponin assays is common. Yet, a differential diagnosis is often demanding and must weigh the timely treatment of an ischemic cause against the risk of an invasive procedure without intervention. Modern cardiac magnetic resonance (CMR) strain sequences such as fast-SENC (fSENC) might support clinical decision-making in identifying predictors of myocardial dysfunction (1). Furthermore, their resolution should be able to differentiate epicardial from endocardial function impairment. This study sought to assess a layer-specific strain approach's diagnostic and prognostic accuracy using circumferential strain. Methods In this board-approved prospective observational study, patients from the emergency department fulfilling rule-in criteria for NSTEMI according to current guidelines received an ultra-fast fSENC CMR independently of standard care (2,3). fSENC was acquired in a single heartbeat acquisition, and global/segmental circumferential strain (GCS) as well as dysfunctional segments were measured. GCS was measured in two layers (epicardial/endocardial = GCSepi/GCSendo). Patients were followed up for two years for the occurrence of cardiovascular death and divided into groups according to their final diagnosis upon discharge. Results 64 patients (51 male) were included, consisting of 25 with NSTEMI, 16 with myocarditis and 23 with other causes of myocardial injury (OMI). GCS was reduced in all patients but with no significant difference between groups (NSTEMI: -14.3±3.8; myocarditis: 15.9±4.6; OMI: 13.9±3.8; p>0.05). GCSendo (-16.3±4.0) was generally lower than GCSepi (-12.5±3.1) in all groups (p < 0.001), but did not differ between groups (p>0.05). Overall, 2-year mortality was low (4.7%). Nevertheless, GCSendo predicted outcome (p = 0.03), unlike GCS. 2-year survival in patients with normal GCS (>-17%) and ≤5 dysfunctional segments was 100.0%. Conclusions Layer-specific circumferential strain is a significant predictor of prognosis. Endo- and epicardial strain is reduced in all types of myocardial injury. For the identification of underlying pathology however, layer-specific circumferential strain did not add incremental value.

Comparison of pulse wave velocity and hypertensive response to exercise in predicting incidence of resistant hypertension

Abstract Background Resistant hypertension (RH) is strongly associated with occurrence of major cardiovascular events and death. Hypertensive response to exercise (HRE) and arterial stiffness estimated by peripheral pulse wave velocity (PWV) are surrogate markers of incident hypertension, whereas their role in predicting RH development remains uncertain. Purpose Explore the predictive role of PWV and HRE in incident RH. Methods A Comparison of HRE and PWV in predicting development of RH was performed in retrospective study with a cohort of 198 patients with known coronary artery disease (CAD). The patients performed two Bruce protocol stress tests (STs) between 01/2009 and 12/2022. The first ST was used to assess HRE and estimated PWV (ePWV) in predicting occurrence of apparent treatment-resistant hypertension (aTRH). ePWV was calculated using age and blood pressure, as previously described (1). HRE response was defined either as systolic BP (SBP) > 210 mmHg or difference between peak and baseline > 60mmHg for men (>190 mmHg or 50 mmHg in women) (2). aTRH was defined as resting SBP above 140mmHg in the last ST despite simultaneous use of ≥3 different antihypertensive agents. The average time between STs was 4±3 years. The incidence of major adverse cardiovascular events (MACE: cardiovascular death, myocardial infarction, heart failure and stroke) were analyzed during the follow-up period of 10±3 years. Logistic and Cox regression models were used in time-to-event analysis. Data presented as: mean ± standard deviation; 95% confidence interval (CI) for odds ratios (OR); significance between groups p<0.05. Results The incidence of aTRH between STs was 15% (n=30), with 48% of them (n=14) receiving ≥4 or more antihypertensive drugs. aTRH vs non-aTRH were similar at baseline for sex (89% male, p=0.67), hypertension (HT, 62%,p=0.08), dyslipidemia (79%, p=0.86), smoke (46%, p=0.50), chronic kidney disease (13%, p=0.39), myocardial infarction (75%, p=0.39), heart failure (4.5%, p=0.40), but not for body mass index (30±3 vs 28±3 kg/m2, p=0.012) and diabetes (60.0 vs 28.6%, p=0.003) that were higher in the aTRH group. The average ePWV was 9.3±1.6 m/s (9.14±1.5 vs 10.2±1.7 m/s, non-aTRH vs aTRH p=0.001); 22.6% patients had HRE (20.4% vs 36.0%, non-aTRH vs aTRH, p=0.084). In contrast to HRE (adjusted OR=1.34, CI 0.4-4.3, p=0.62), ePWV was correlated with aTRH (adjusted OR=2.0, CI 1.1-4.1, p=0.024) after adjusting for age, comorbidities and anti-HT drugs, with an area under the ROC curve of 0.7 (CI 0.6-0.8). Both aTHR (OR=2.6, CI 1.2-5.8, p=0.017) and ePWV (adjusted OR=1.3, CI 1.2-5.8, p=0.024) were associated with MACE. Conclusion ePWV is a simple and robust marker that outperforms HRE in predicting aTRH and MACE in CAD patients. Higher ePWV values were independently associated with the incidence of aTRH. This study strengthens the importance of developing new strategies to control arterial stiffness in the treatment of RH and prevention of MACE.

Incremental prognostic value of fully automatic LVEF measured at stress using machine learning

Abstract Background Cardiovascular magnetic resonance (CMR) is the gold standard to measure left ventricular ejection fraction (LVEF), and novel artificial intelligence-based automatic analyses have been proposed for less user interaction and time saving. However, whether automatic LVEF delivers similar information for risk stratification remains unknown. Purpose To assess the prognostic value for all-cause mortality of LVEF measured by stress CMR using a fully automatic machine learning algorithm without human correction. Methods Between 2016 and 2018, all consecutive patients referred for vasodilator stress CMR were included and followed for the occurrence of all-cause death. A fully automatic machine learning algorithm was trained on 3,700 scans and validated on 1,719 unseen CMR studies (MAGNETOM Aera and Skyra, Siemens Healthcare, Erlangen, Germany) to identify end-diastolic and end-systolic phases and segment LV volumes from short-axis cine images at stress. The algorithm combines multiple deep learning networks for detection and segmentation with an active contours approach. Manual and automatic LVEF measured at stress were compared with the paired Wilcoxon test, Pearson correlation and Bland-Altman analysis. Cox regressions were performed to determine the prognostic value of automatic LVEF measured at stress. Results Among 9,883 included patients included to this study, the automatic LVEF was successfully computed in 9,712 (98.3%) patients (66.6% male, mean age 66±12 years). The agreement between manual and automatic LVEF was good (bias = -0.01%, 95% limits of agreement, -6.7% to 6.7%; Pearson’s correlation coefficient r=0.94). A total of 504 (5.2%) deaths were observed during a median (IQR) follow-up period of 4.5 (3.7-5.2) years. Both manual and automatic volumetric assessments showed similar impact on outcome in univariate analyses (manual LVEF per 5%: hazard ratio [HR], 0.80 [95% CI 0.77–0.83]; p<0.001; automatic LVEF per 5%: HR, 0.84 [95% CI, 0.81–0.86]; p<0.001) and multivariable analyses (manual LVEF per 5%: HR, 0.81 [95% CI, 0.78–0.84]; p<0.001; automatic LVEF per 5%: HR, 0.84 [95% CI, 0.82–0.87]; p<0.001). Fully automatic stress LVEF showed an incremental prognostic value to predict all-cause mortality above all traditional risk factors, LVEF measured at rest, the presence of inducible ischemia and LGE (C-statistic improvement: 0.04; NRI=0.221; IDI=0.049; all p<0.001). Conclusions Automatic LVEF is equally predictive of all-cause mortality compared to manual LVEF, and has an incremental prognostic value compared to traditional risk factors, and other stress CMR parameters. Figures: Figure 1: Linear regression plots (A) and Bland-Altman plots (B) comparing stress LVEF measured by experts (LVEFexpert) and computed by fully-automated artificial-intelligence algorithms (LVEFAI). Figure 2: Kaplan-Meier curves for MACE stratified by fully-automated LVEF value. Test comparing the three groups is based on the log-rank test.

GLP-2 predicts cardiovascular outcomes in patients with myocardial infarction and increases atherosclerosis in mice

Abstract Background GLP-1 and GLP-2 (glucagon-like peptide-1/2) are incretin hormones that are co-secreted from intestinal L-cells in response to food intake and inflammatory stimuli. While GLP-1 is known to induce postprandial insulin secretion and to improve cardiovascular outcomes in patients with diabetes, GLP-2 enhances intestinal nutrient absorption. GLP-2 agonists are clinically used for the treatment of patients with short bowel syndrome. The relevance of GLP-2 beyond the gut is not well understood. The aim of this study was to investigate the role of GLP-2 for cardiovascular disease (CVD). Methods Total GLP-2 levels were assessed at time of admission in 918 patients with myocardial infarction presenting with acute chest pain, among them 597 patients with NSTEMI and 321 with STEMI. The primary composite outcome of the study was the first occurrence of all-cause death, nonfatal myocardial infarction, or nonfatal stroke (3-P-MACE) with a median follow-up of 311 days. To induce atherosclerosis, Glp2r−/− or WT mice were injected with PCSK9 virus and fed a diet high in cholesterol (HCD) for 12 weeks. Results Kaplan-Meier survival plots (separated by the median of GLP-2 with a cut-off value of 4.4 pM) and univariable cox regression analyses found GLP-2 values to be associated with adverse outcome (3-P-MACE and all-cause mortality; logarithmized GLP-2 values HR: 2.87; p<.0001). Further adjustment for age, sex, smoking, hypertension, hypercholesterinemia, previous CVD and diabetes mellitus did not affect this association (logarithmized GLP-2 values HR: 2.66; p=0.0055). Receiver operating characteristic curve (ROC) analyses illustrated that GLP-2 is a strong indicator for early events (area under the curve of the combined endpoint at 7 days: 0.74; 14 days: 0.76; 30 days: 0.76; 6 months: 0.72), which proved to be superior to Troponin T and hs-CRP. To asses the functional role of GLP-2 in CVD in an experimental approach we injected Glp2r−/− or WT mice PCSK9 virus (to induce functional Ldlr-deficiency and hypercholesterolemia) and fed these mice a HCD. After 12 weeks Glp2r−/− mice compared to WT littermates presented with a significant reduction in plaque volume and lesion size. While body weight and circulating leukocyte numbers (FACS analysis) were unaffected, Glp2r−/− mice had lower cholesterol levels. Conclusion Circulating GLP-2 levels are associated with cardiovascular events in patients with acute myocardial infarction while inactivation of the GLP-2 system reduces atherosclerosis in mice. Future studies are needed to investigate whether the GLP-2 receptor might provide a novel therapeutic target for cardiovascular disease.

The framing of time-dependent machine learning models improves risk estimation among young individuals with acute coronary syndromes

Abstract Introduction Acute coronary syndrome (ACS) is a common cause of death in individuals older than 55 years. Although younger individuals are less frequently seen with ACS, this clinical event shows high recurrence rates and triggers considerable economic burden. Young individuals with ACS (yACS) are usually underrepresented and show idiosyncratic epidemiologic features compared to older subjects. These differences may justify why available risk prediction models usually penalize yACS with higher false positive rates compared to older subjects. We hypothesized that exploring temporal framing structures such as prediction time, observation windows and subgroup-specific prediction, could improve time-dependent prediction metrics. More specifically, we evaluated potential improvements in risk prediction quality among yACS by (i) developing models specifically in yACS versus a global cohort; (ii) splitting predictive rules into short- and long-term prediction windows [STWm and LTWm] versus a global follow-up model (GFm). Methods We included 6341 consecutive subjects with ACS (2242 with yACS) admitted into public hospitals in a large city in Brazil who undergone coronarography up to 48h after hospital admission from 2011 to 2020. The observation window in STWm and GFm included the first 48h upon hospital admission, and LTWm included all in-hospital information. yACS cohort was divided into train/validation-set (70%, n=1569) and test-set (30%, n=673); global cohort was divided in training/validation-set (70%, n=4439) and test-set including the 673 yACS subjects. Models were repeated over five cross-validation folds and then assessed in the test-set. C-statistics was the evaluation metric for STWm and time-dependent concordance (Ctd-index) for LTWm. STWm evaluated the occurrence of in-hospital cardiovascular deaths and recurrent ACS (MACE) and LTWm estimated events occurring post-discharge from index ACS hospitalization considering time-to-event with competing risks (MACE versus non-cardiovascular deaths). Results Among yACS and older subjects, respectively, in-hospital MACE occurred in 180 and 493 individuals, post-discharge MACE in 454 and 881; and post-discharge non-cardiovascular death in 47 and 285 after 6.67 years (95%CI 5.59-7.24) of follow-up. The best strategy was to design models specifically in yACS individuals combining STWm and LTWm. Among yACS subjects, STWm and LTWm yielded a C-statistics [0.921 (95%CI 0.889-0.953)] and Ctd-index [0.722 (95%CI 0.678-0.760)], respectively, while the best Ctd-index in GFm was 0.681 (95%CI 0.654-0.703). There was very low concordance among top predictors of MACE for prACS versus global cohort, as well as for STWm versus LTWm. Conclusions Predictive accuracy for adverse clinical events was optimized by using specific rules for yACS and splitting short-term and long-term prediction windows, leading to the detection of 80% of events, compared to 69% by using a rule designed for the global cohort.

Identification of novel risk profiles for ventricular arrythmias in hypertrophic cardiomyopathy through clustering analysis including left ventricular strain data

Abstract Aims The excess mortality in hypertrophic cardiomyopathy (HCM) patients is mainly attributed to the occurrence of ventricular arrythmias (VA) and sudden cardiac death (SCD). The prediction of VA remains challenging and could be improved. The aim of the study was to characterize VA risk profile in HCM patients through clustering analysis combining clinical and conventional imaging parameters with information derived from left ventricular longitudinal strain analysis (LV-LS). Methods A total of 434 HCM patients (65% men, mean age 56 years) were retrospectively included from two referral centers from two different countries and followed longitudinally (mean duration 6 years). Mechanical and temporal parameters were automatically extracted from the LV-LS segmental curves of each patient in addition to conventional clinical and imaging data. A total of 287 features were analyzed using a clustering approach (k-means). The first endpoint for ventricular arrythmias (VA) included suspected SCD, aborted cardiac arrest, appropriate ICD therapy (AIT), sustained ventricular tachycardia (SVT) and non-sustained ventricular tachycardia (NSVT) during follow-up. Results 4 clusters were identified with a higher rhythmic risk for cluster 1 and 4 (VA rates of 26%(28/108), 13%(13/97), 12%(14/120), and 31%(34/109) for cluster 1,2,3 and 4 respectively) (Figure 1). These 4 clusters have been mainly separated based on LV strain parameters with severe and homogeneous decrease of myocardial deformation for cluster 4 (global longitudinal strain (GLS) -11%), a small decrease for cluster 2 and 3 (GLS -17.2 and -16.3%, respectively) and a marked mechanical and temporal dispersion for cluster 1 associated with a moderate decrease of the GLS (-15.3%; p <0.0001 for GLS comparison between clusters) (Figure 2). Patients from cluster 4 had the most severe phenotype (mean LV mass index 123 vs. 112 g/m²; p=0.0003) with marked diastolic dysfunction (left atrial volume index (LAVI) 46.6 vs. 41.5 ml/m² for others clusters; p=0.04) and impaired exercise capacity (% predicted peak work 58.6 vs. 69.5%; p= 0.025). Patient from cluster 2 had the less severe phenotype (mean LV mass index 99.6 vs. 121 g/m²; p=0.0001 and LAVI 37.2 vs. 44.3 ml/m²; p=0.04). Patients from cluster 3 and 1 had a moderate phenotype and were older in cluster 3 (mean age 62.1 vs. 54.1 years; p < 0.0001) and had more obstructive form in cluster 1 (peak gradient LV outflow tract ≥ 30 mmHg for 36 vs. 23% of patients; p=0.046) with a larger left atrium size (LAVI 45.8 vs. 41.7 ml/m²; p=0.0023). Conclusion Using a clustering approach processing LV-LS parameters in HCM patients identified 4 clusters with specific LV-strain patterns and different rhythmic risk level. In the future, the automatic extraction and analysis of LV strain parameters could help to improve the risk stratification for SCD in HCM patients.Figure 1:Survival curvesFigure 2:Different strain patterns

Prognostic value of monocyte-to-high-density lipoprotein-cholesterol ratio for all-cause mortality and heart failure in new-onset atrial fibrillation: a population-based cohort study

Abstract Background A growing body of evidence suggests that inflammation plays a role in the onset and progression of atrial fibrillation (AF). Monocyte-to-high-density lipoprotein-cholesterol ratio (MHR) has emerged as a novel and accessible biomarker that reflects both inflammation and oxidative stress. Previous studies have demonstrated the predictive value of MHR in several cardiovascular diseases including ischaemic stroke and acute coronary syndrome, but the association between MHR and adverse outcomes of AF remains unclear. Purpose With this study, we aimed to investigate the relationship of MHR with all-cause mortality and incident heart failure in patients with new-onset AF. Methods Patients with newly diagnosed AF from 1998-2021 (n=80,911) were included in this Hong Kong population-based cohort study. MHR was obtained by dividing fasting monocyte count by high-density lipoprotein-cholesterol, and patients were grouped according to MHR tertiles. We followed up patients until occurrence of outcomes, death or 1st September, 2022. The primary outcome was all-cause mortality, and the secondary outcome was incident heart failure. We evaluated the associations of MHR with all-cause mortality and heart failure both on a continuous scale using restricted cubic spline curves and by categories using multivariate Cox proportional hazards regression model. Results The median age of the cohort was 77.9 years old and 41,536 (51.3%) were male. Over a median follow-up of 3.7 years, 43,902 (54.3%) deaths and 14,114 (17.4%) incident heart failure occurred. The restricted cubic spline curves illustrated that MHR had a non-linear association with all-cause mortality and heart failure. Univariate Cox regression indicated that increased MHR at tertiles 2 and 3 were significantly associated with higher risks of all-cause mortality (HR: 1.06 [1.04-1.09], P<0.001, 1.25 [1.22-1.28], P<0.001, respectively) and new onset heart failure (1.07 [1.02-1.11], P=0.002, 1.23 [1.18-1.28], P<0.001, respectively) when compared to those in tertile 1. MHR remained a significant predictor of mortality (tertile 2 HR: 1.06 [1.04-1.09], P<0.001, tertile 3 HR: 1.22 [1.19-1.25], P<0.001) and heart failure (tertile 2 HR: 1.06 [1.02-1.10], P=0.007, tertile 3 HR: 1.21 [1.16-1.26], P<0.001) after multivariable adjustment. Conclusion MHR is a promising prognostic biomarker for all-cause mortality and heart failure in patients with new-onset AF.

Functional volume distribution in tricuspid regurgitation associated right heart failure

Abstract Background Tricuspid regurgitation (TR) associated right heart failure is a significant challenge, and while tricuspid edge-to-edge repair (TEER) has been suggested to improve outcomes, patients remain at substantial residual risk. Thus, adjunctive therapies to treat associated right heart failure are warranted. Sympathetically mediated venoconstriction with subsequent changes in functional volume distribution with increases in stressed blood volume (SBV) ( the volume compartment which generates intravascular pressure) has been shown to importantly mediate hemodynamic derangements in heart failure and might pose an attractive adjunctive treatment target (e.g. by means of splanchnic denervation). Objectives This study aimed to elucidate the determinants of unfavorable functional volume distribution in patients with TR-associated right heart failure and investigate the prognostic role of SBV after TEER. Methods and Results A total of 279 patients underwent right heart catheterization (RHC) prior to TEER. SBV was estimated (eSBV) from hemodynamic variables fit to an extensively validated and comprehensive cardiovascular model. eSBV was associated with obesity, renal and hepatic dysfunction, and cardiac remodeling (p < 0.05 for all). Hemodynamically, eSBV correlated with pulmonary artery (PA) and cardiac filling pressures, as well as right ventricular-PA coupling (p < 0.05 for all). After TEER, patients with eSBV above the median demonstrated less reduction in right atrial pressures, peripheral edema, and ascites compared to lower eSBV patients (p < 0.05 for all). Higher eSBV was a powerful predictor of the occurrence of death and heart failure hospitalization during a median follow-up of 618 days (p < 0.05 for all) independent of all clinical, imaging, and invasive hemodynamic parameters. Conclusion In severe TR, eSBV is associated with obesity, renal and liver dysfunction, more severe heart failure, attenuated reduction of venous congestion after TEER, as well as adverse clinical outcomes. Estimation of SBV should be incorporated in future trials in the field to identify patients in need of adjunctive therapies and test its role as a potential treatment target.

Prognostic value of pulmonary hypertension in patients with advanced heart failure evaluated fort heart replacement therapy in the light of new definition of pulmonary hypertension

Abstract Background Pulmonary hypertension (PH) due to left heart disease is a common complication in heart failure (HF) and is associated with increased mortality. The 2022 ESC Guidelines updated the hemodynamic definition of PH lowering the threshold to mean pulmonary artery pressure (mPAP) >20 mmHg. The relevance of this classification has not been fully explored in the setting of advanced heart failure. Purpose The aim of this study was to investigate epidemiology and clinical outcomes of PH according the 2022 definition in patients with advanced HF candidate to heart replacement therapy (HRT) defined as heart transplantation (Htx) or left ventricular assist device (LVAD) implantation. Methods This study is a retrospective analysis of all adult (> 18 years old) patients that underwent HRT evaluation with an available right heart catheterization from 2003 to 2018. Patients were selected based on HLA typing as a proxy for HRT evaluation. Patients were divided into groups based on the presence of PH with mPAP < 20 mmHg, 21-24 mmHg or > 25 mmHg) to define the impact of the revised classification. Updated definition was then applied to investigate association with prognosis. Study outcome was the composite occurrence of death, urgent HTx or LVAD implantation. Patients were stratified into 3 different eras to account for the extent of the study period. Univariate and multivariate analysis was used to detect risk factors correlated to outcome. Results 625 patients were screened, of whom 619 had an available RHC and were included in the study. Median follow-up was 15 months (IQR 5-39). With the threshold of mPAP > 20 mmHg, 450 patients (73%) had PH as compared to 366 (59%) with the previous definition. Survival from endpoint was significantly lower in both patients with mPAP 21-24 [1 year: 87%; 5-years 53%; OR 1,7 (1,3-3,8); p = 0.005] and > 25 mmHg [1 year 81%, 5 years 50%; OR 2,7 (1,8-4,2); p< 0,001], as compared to those without PH (1 year 91%, 5 years 78%). No difference was found between the groups of increased mPAP. Applying the 2022 definition, 122 (19%) patients had isolated isolated pC-PH, 320 (52%) combined pC-PH and 8 a form of pre-capillary PH. Isolated pC PH and combined pC PH both correlated with worse outcome (OR respectively 2,3; p = 0.0017 and 2,7 p<0.001). In patients with combined PH, PVR > 3 WU was associated with worse survival (88% vs 76% at 1t year). Conclusion In this study of patients with advanced HF evaluated for HRT, the 2022 hemodynamic definition of PH identified an additional 13% of patients. Survival was lower in patients with mPAP > 20 mmHg and these finding support the revised threshold and its association with prognosis in this population. In patients with combined PH, PVR > 3 WU is associated with worse outcomes. In advanced HF, this threshold may retain better prognostic value.

Mortality prediction in patient with atrial fibrillation and 0 or 1 nongender-related CHA2DS2-Vasc risk factor using machine learning: a French nationwide study

Abstract Background Atrial fibrillation is associated with important mortality included in patients with low or intermediate thromboembolic risk. Usual clinical risk scores are challenged in this specific population and predict only modestly mortality. Machine learning approach helps to identify new risk factors and outperform existing tools for the prediction of outcomes in atrial fibrillation patients. Purpose This study aimed to developpe a machine learning model for the prediction death occurrence within the year following atrial fibrillation diagnosis and to assess performances in patients with 0 or 1 nongender-related CHA2DS2-Vasc risk factor compared to previously described clinical scores. Methods We used for this purpose a nationwide cohort of 2,435,541 newly diagnosed atrial fibrillation patients seen in all the French hospitals from 2011 to 2019. Among 110 variables, the 18 most predictive variables were identified and selected using a Random Forest algorithm as adding any other variable did not improve prediction (Figure 1). Three machine learning models (logistic regression, random forests, deep neural networks) were trained to predict mortality within the first year on a train set (70% of the cohort). The best model was selected to be evaluate on the validation set (30% of the cohort). We finally compared our best model with previously published scores in patients with 0 or 1 nongender-related CHA2DS2-Vasc risk factor using the C index. Results Among atrial fibrillation patients, 373,155 (15.32%) had 0 or 1 nongender-related risk factor. Within the first year following AF diagnosis, 23,857 patients (6.39%) died after a mean time of 86 (SD 26) days. After training, the best machine learning model selected was a deep neural network with a C index of 0.915 (95% CI, 0.905- 0.925) on the validation set. Compared to traditional clinical risk scores, the deep neural network model was significantly superior to the CHA2DS2-VASc and HAS-BLED scores, and dedicated scores such as Charlson Comorbidity Index and Hospital Frailty Risk Score to predict death within the year following AF diagnosis (C indexes: 0.521; 0.633; 0.849; 0.800 respectively. P<0.0001) (Figure 2, Panel A). The ability to predict AF was improved as shown by the net reclassification index and integrated discriminatory improvement increase (P<0.0001, respectively) and decision curve analysis (Figure 2, Panel B). Conclusion Patients with atrial fibrillation and 0 or 1 nongender-related CHA2DS2-Vasc risk factor remain at risk of mortality within the first year of the diagnosis. A ML approach may help clinicians to better risk stratify AF patients with low or intermediate thromboembolic risk at high risk of mortality.Figure 1.Feature importanceFigure 2.ROC and decision curves

Penalised semi-parametric copula method for semi-competing risks data: application to hip fracture in elderly

Abstract Hip fracture is a severe complication in the elderly. The affected people are at a higher risk of second fracture and death occurrence, and the best treatment for hip fractures is still being debated. Aside from the treatment, many factors, such as comorbidity conditions, may be associated with second fracture and death occurrence. This study aims to identify effective treatments and important covariates and estimate their effects on the progression of second fracture and death occurrence in hip fracture elderly patients using the semi-competing risks framework, because death dependently censors a second fracture but not vice versa. Due to the complex semi-competing risks data, performing variable selection simultaneously for second fracture and death occurrence is difficult. We propose a penalised semi-parametric copula method for semi-competing risks data. Specifically, we use separate Cox semi-parametric models for both margins and employ a copula to model the two margins’ dependence. We develop a coordinate-wise optimisation algorithm that takes into account the data structure and copula function’s complexities. Simulations show that the proposed method outperforms the traditional penalised marginal method. We apply the proposed method to a population-based cohort study of hip fracture elderly patients, providing new insights into their treatment and clinical management.

Abstract 15100: Long-Term Clinical Outcomes Following Percutaneous Coronary Intervention in the Super Elderly Patients Aged Over 90 Years

Background: In aged society, percutaneous coronary intervention (PCI) for super-elderly patient is not rarely performed in clinical practice. However, data regarding the clinical features and outcomes among the population are still limited. Aim: To investigate the patient characteristics and long-term clinical outcomes in nonagenarians who underwent PCI. Methods: This was a multicenter observational study, enrolling 402 nonagenarian patients who underwent PCI across 10 hospitals between 2011 and 2020. This study included the patients presented with acute coronary syndrome (ACS) and chronic coronary syndrome (CCS). Clinical outcomes including the occurrence of all-cause and cardiac deaths were investigated. Results: In overall 402 patients (mean age 91.9±2.0 years, 48.3% male), regarding coronary risk factors, 74.6% had hypertension, 25.4% diabetes mellitus, and 56.7% dyslipidemia. Majority of patients (77.9%) were ACS, mainly ST-segment elevation myocardial infarction (53.2%), and 22.1% CCS. During hospitalization [median 14 days (interquartile range, 6-25 days)], in-hospital death occurred in 12.4%. The rate was significantly higher in ACS patients than CCS patients (15.3% vs. 2.2%, p<0.001). The cause of death was mainly cardiac death (96.0%). The median follow-up period was 544 days (interquartile range, 72-1171 days). The estimated cumulative incidence rates of all-cause death were 24.3%, 39.5% and 60.4% at 1-year, 3-years, and 5-years respectively. The rates of cardiac death were 18.0%,26.5% and 39.2% at 1-year, 3-years, and 5-years, respectively. No significant difference was observed in the occurrence of all-cause death between the patients with ACS and CCS. Regarding causes of death after discharge, 44.1% were cardiac causes mostly account for heart failure and sudden death, and 55.9% were non-cardiac causes mainly account for infection and cancer. Conclusion: This study highlights the clinical features and long-term clinical course of nonagenarian patients who underwent PCI in the real-world setting. The patients presented with ACS had higher rate of in-hospital death than CCS, and the cumulative mortality increased approximately linearly after discharge, regardless of ACS or CCS.

Abstract 12128: Catheter Ablation Outperforms Implantable Cardioverter Defibrillator Therapy in Improving Arrhythmic Outcomes of Brugada Syndrome

Background: Brugada syndrome (BrS) is characterized by ventricular arrhythmias that pose a significant risk to affected individuals. While ICD therapy is the primary treatment, it does not prevent VF episodes. Catheter ablation (CA) has shown promise in improving arrhythmic outcomes. This study aims to compare the efficacy of CA with ICD therapy in symptomatic BrS patients. Methods: A total of 49 symptomatic BrS patients were enrolled, with 21 patients undergoing CA and 28 patients receiving ICD therapy. Substrate modification techniques, including endocardial and epicardial approaches, were utilized along with VF-triggering PVC ablation strategies. The primary outcomes assessed were the occurrence of VF episodes and sudden cardiac death during the follow-up period. Results: The study population had a mean age of 44.3±10.4 years, with 44 patients (89.8%) being male. Among the participants, 40 (81.6%) exhibited the typical type 1 BrS electrocardiogram pattern, and 12 (24.5%) had a positive SCN5A mutation. VF-triggering PVCs were successfully ablated in 3 patients (14.3%), while VF substrates were eliminated in 18 patients (85.7%). Epicardial ablation was performed in 14 patients (66.7%). During a median follow-up of 46.2 (15.6-68.8) months, the primary outcomes occurred more frequently in the ICD group compared to the CA group (4.8% vs. 57.1%, Log-rank P = 0.006). Conclusion: Our findings suggest that CA is a more effective therapy for improving arrhythmic outcomes in symptomatic BrS patients compared to ICD implantation. These results highlight the potential of CA as a first-line therapeutic approach for managing symptomatic BrS.