Cox Regression Research Articles

Implantable loop recorders in children and adolescents with Brugada syndrome: the YoungBruLoop study

Abstract Background Young (<18 years of age) patients with Brugada syndrome (BrS) are often underrepresented in BrS studies and their management, especially related to syncopal episodes, remains unclear. Purpose To describe the arrhythmia prevalence and clinical implication derived from continuous rhythm monitoring by implantable loop recorder (ILR) among patients younger than 18 years of age, and to assess the etiology behind syncope of undetermined origin. Methods A total of 147 BrS patients with ILR were enrolled in 12 international centers and divided into pediatric (age <12 years; n=77, 52%) and adolescents (age 13 to 18 years; n=70, 48%). Results Mean age was 11.3 years (36.1% females, 21.1% spontaneous type I ECG). Forty-six patients (31.2%) underwent ILR implant due to syncope. Over a median follow-up of 3.6 years, an arrhythmic event was recorded in 22.4% of patients and in the vast majority of cases it was of non-ventricular origin (44% atrial, 47% bradyarrhythmias). Predictors of arrhythmias at univariate Cox Regression analysis were spontaneous type I ECG (HR 2.1 - 95%C.I. 1.1-4.1), history of syncope (HR 3.1 - 95%CI 1.5-6.3) and age >12 years (HR 2.0 - 95%C.I. 1.0-3.3). Ventricular arrhythmias occurred in 4 patients, all with spontaneous BrS, and were related to fever in half of cases. In patients with recurrent syncope, the prevalence of truly arrhythmic syncope was 17.8%, and it was due to brady-, atrial- and ventricular arrhythmias in 40%, 20% and 40% of cases, respectively. Conclusions Continuous rhythm monitoring with ILRs in BrS pediatric patients detects a broad range of heart rhythm disturbances including life-threatening arrhythmias. Ventricular arrhythmias occur predominantly in patients with spontaneous type I ECG and in half of cases are fever-related. Despite the young age, brady- and atrial arrhythmias are overall frequent and represent the cause of arrhythmic syncope in 60% of patients. Young BrS patients with syncope of undetermined origin may benefit from ILR implant.

Integrated analysis of bulk and single-cell RNA sequencing reveals the impact of nicotinamide and tryptophan metabolism on glioma prognosis and immunotherapy sensitivity

BackgroundNicotinamide and tryptophan metabolism play important roles in regulating tumor synthesis metabolism and signal transduction functions. However, their comprehensive impact on the prognosis and the tumor immune microenvironment of glioma is still unclear. The purpose of this study was to investigate the association of nicotinamide and tryptophan metabolism with prognosis and immune status of gliomas and to develop relevant models for predicting prognosis and sensitivity to immunotherapy in gliomas.MethodsBulk and single-cell transcriptome data from TCGA, CGGA and GSE159416 were obtained for this study. Gliomas were classified based on nicotinamide and tryptophan metabolism, and PPI network associated with differentially expressed genes was established. The core genes were identified and the risk model was established by machine learning techniques, including univariate Cox regression and LASSO regression. Then the risk model was validated with data from the CGGA. Finally, the effects of genes in the risk model on the biological behavior of gliomas were verified by in vitro experiments.ResultsThe high nicotinamide and tryptophan metabolism is associated with poor prognosis and high levels of immune cell infiltration in glioma. Seven of the core genes related to nicotinamide and tryptophan metabolism were used to construct a risk model, and the model has good predictive ability for prognosis, immune microenvironment, and response to immune checkpoint therapy of glioma. We also confirmed that high expression of TGFBI can lead to an increased level of migration, invasion, and EMT of glioma cells, and the aforementioned effect of TGFBI can be reduced by FAK inhibitor PF-573,228.ConclusionsOur study evaluated the effects of nicotinamide and tryptophan metabolism on the prognosis and tumor immune microenvironment of glioma, which can help predict the prognosis and sensitivity to immunotherapy of glioma.

Prognostic role of remnant cholesterol and traditional cardiovascular risk factors in young adults: results of long-term follow-up of a cohort of 30-year-old norwegians

Abstract Background There are limited data on the prevalence and impact of traditional cardiovascular (CV) risk factors among young adults. In addition, more knowledge on novel CV risk factors is needed to explain the residual risk beyond that of the traditional risk factors. Increasing evidence suggest a causal role of remnant cholesterol (RC) in the development of atherosclerotic cardiovascular disease (CVD) and subsequent clinical events. However, the role of RC in young adults is unresolved. Purpose We aimed to evaluate the prevalence of traditional risk factors and the respective sex-differences in young adults, as well as their association with long-term CV events. Further, we hypothesized that higher RC concentrations are associated with impaired CV prognosis. Methods In year 2000, all 30-year-old inhabitants of our city were invited to a cross-sectional study including assessment of health status, anthropometric measurements, and non-fasting blood samples. RC was calculated as total cholesterol minus (LDL-C + HDL-C). Long-term clinical follow-up was performed through linkage with mandatory national registries, 22 years after inclusion. The primary outcome was a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal ischemic stroke, hospitalization for unstable angina and coronary revascularization. Results A total of 5950 individuals were included (56% women). At baseline, men displayed significantly higher systolic and diastolic blood pressure, total cholesterol, LDL-C and triglycerides, as compared with women (Table 1). Also, men had higher levels of RC (Table 1). During a mean follow-up time of 22 years, 108 events (1.8%) occurred. In multivariable Cox regression analysis, non-West-European ancestry (adjusted [a] HR 1.76, 95% confidence interval [CI] 1.03-2.99), diabetes mellitus (aHR 6.39, 95% CI 2.52-16.2), systolic blood pressure (aHR 1.03, 95% CI 1.01-1.04), and LDL-cholesterol (aHR 1.37, 95% CI 1.11-1.68) were associated with an increased risk of CV events during long-term follow-up. Female gender was associated with a reduced risk of CV events (aHR 0.38, 95% CI 0.23-0.64), whereas smoking status did not show any significant association. RC was identified as a significant predictor of CV events (aHR 1.55, 95% CI 1.11-2.18, per 1.0 mmol/L increase). The highest RC quartile (mean RC: 1.1 mmol/L), had the highest event rate (Figure 1, p<0.001 with log-rank test). Conclusion This study uncovers significant sex-differences in modifiable CV risk factors among young adults at the age of 30, which are associated with increased risk for long-term CV events. Interestingly, increasing concentrations of RC at the age of 30 were strongly associated with impaired long-term CV outcome and should be accounted for in early risk prediction.Baseline characteristics.Remnant cholesterol and CVD events.

Implications of renal function on adverse clinical events in patients with atrial fibrillation: a comparative analysis of VKA and NOAC therapy - Insights from the GLORIA-AF Registry Phase III

Abstract Background Renal function, as assessed by creatinine clearance (CrCl), plays a crucial role in determining the efficacy and safety of oral anticoagulant (OAC) therapy in patients with atrial fibrillation (AF). Purpose To investigate the relationships between CrCl and the risk of clinical adverse events in patients with AF receiving OAC therapy, comparing the safety profiles of vitamin K antagonists (VKA) and non-vitamin K antagonist oral anticoagulants (NOACs). Methods Anticoagulated AF patients from the prospective Global Registry on Long-Term Oral Anti-Thrombotic Treatment in Patients with Atrial Fibrillation (GLORIA-AF) registry Phase III were studied. CrCl was calculated for renal function, according to Cockcroft-Gault equation. Restricted cubic spline (RCS) were used to explore the nonlinear association between adverse end events and CrCl, comparing VKA and NOAC therapy. Cox regression models were used to analysis the associations between adverse end events and OAC therapy in patients with different CrCl levels, adjusted by clinical features and previous disease. Patients were followed up for the composite outcome (all-cause death, thromboembolism and major bleeding), all-cause death, cardiovascular disease (CVD), major bleeding, myocardial infarction (MI) and stroke. Results In 10,594 AF patients (mean age 70.35 ± 9.92 years; 55% male; 73% on NOAC), RCS analysis revealed decreased risks of all cause death, composite outcomes and CVD with increasing CrCl in patients with CrCl < 80 mL/min. Multivariate Cox models indicated that NOAC therapy associated with lower risk of all cause death (HR 0.68, 95% CI 0.58-0.78), composite outcomes (HR 0.77, 95% CI 0.68-0.86), CVD (HR 0.7, 95% CI 0.56-0.87), major bleeding (HR 0.74, 95% CI 0.61-0.91) in AF patients. For CrCl > 95 mL/min, a lower risk of all cause death (HR 0.56, 95% CI 0.38-0.82), composite outcomes (HR 0.68, 95% CI 0.51-0.91) and major bleeding (HR 0.54, 95% CI 0.35-0.85) were associated with NOAC therapy, vs. VKA. For CrCl < 30 mL/min, a lower risk of all cause death (HR 0.47, 95% CI 0.28-0.81), composite outcomes (HR 0.56, 95% CI 0.35-0.89) and CVD (HR 0.43, 95% CI 0.20-0.90) were related to NOAC therapy. No significant difference in outcomes between VKA and NOAC were found in patients with moderate CrCl. Conclusion Increasing CrCl were associated with decreased risk of adverse clinical events, including all-cause death and CVD in anticoagulated AF patients. For patients with CrCl >= 95 and < 30, NOAC therapy, was associated with lower risks of adverse outcomes.Figure 1Figure 2

Both fibrosis-4 index and fibrosis-5 index can predict the prognosis of patients after percutaneous coronary intervention

Abstract Backgrounds: The Fibrosis-4 (FIB-4) index and Fibrosis-5 (FIB-5) index are non-invasive indicators reflecting liver fibrosis. Previous studies show their association with acute heart failure and myocardial infarction prognosis. However, there are few reports on the relationship between the two indices and the prognosis of patients after percutaneous coronary intervention (PCI). Purpose This study aims to explore and compare the predictive value of both indices for PCI patient prognosis. Method Data for this study were obtained from a retrospective cohort comprising patients admitted to and discharge d from 72 secondary and tertiary hospitals between 2010 and 2023. Inclusion criteria comprised patients undergoing PCI during hospitalization. The initial test results of these patients after admission were collected, and the FIB-4 (FIB-4 = age (years) × aspartate aminotransferase (AST [U/L]) / (platelets [10^9/L] × alanine aminotransferase [ALT {U/L}]½) and FIB-5 (FIB-5 = [albumin (g/L) × 0.3 + platelet count (10^9/L) × 0.05] - [alkaline phosphatase (U/L) × 0.014 + AST/ALT ratio × 6 + 14]) indices were calculated. Patients were divided into low (N = 83082), medium (N = 16618), and high (N = 7932) FIB-4 groups, as well as low (N = 18642), medium (N = 12106), and high (N = 76884) FIB-5 groups based on predefined cutoff values. The primary endpoint was one-year cardiovascular mortality, with secondary endpoints including one-year all-cause mortality and one-year recurrent myocardial infarction. Results The study included 107,632 patients after PCI whose FIB-4 index and FIB-5 index could be simultaneously calculated during hospitalization. Multivariable Cox regression analysis revealed that compared to the low FIB-4 group, both the high FIB-4 group (aHR 1.935; 95%CI 1.592-2.353) and the medium FIB-4 group (aHR 1.487; 95%CI 1.251-1.768) had an increased risk of one-year cardiovascular death (P0.05). Conclusions The present study indicated that both FIB-4 and FIB-5 could be used to predict the prognosis of patients after PCI. High FIB-4 index and low FIB-5 index were predictive factors for 1-year cardiovascular death, 1-year all-cause death, and 1-year recurrent myocardial infarction in patients after PCI, with no statistical difference in predictive value between the two.

The Association Between Dietary Vitamin C and Sleep Disorders: A Cohort Study Based on UK Biobank

Objective: Approximately 30% of adults globally suffer from sleep disorders. However, there are few longitudinal studies on the association between dietary vitamin C and sleep disorders. This study aimed to investigate the association between dietary vitamin C intake and various types of sleep disorders, including sleep apnea and insomnia. Methods: We enrolled 68,221 participants from the UK Biobank. Dietary vitamin C intake was assessed using a 24 h dietary recall questionnaire. We employed a Cox regression model to assess the association between dietary vitamin C and sleep disorders and used restricted cubic spline models to investigate potential nonlinear relationships. Stratified and sensitivity analyses were also conducted to validate the findings. Results: The results indicated that vitamin C intake at the Q4 level (132.88–191.51 mg/d) was significantly associated with a reduced risk of sleep disorders, with an HR (95% CI) of 0.78 (0.65–0.94), and against sleep apnea, with an HR (95% CI) of 0.75 (0.62–0.92). The protective effect persisted significant in stratified analyses of men and those aged ≤ 60 years; the results were consistent in the sensitivity analyses. Conclusions: Our findings suggest that sufficient dietary vitamin C intake may help to prevent sleep disorders.

Mid-regional pro-adrenomedullin is an independent predictor of cardiovascular outcomes in cardiac surgery, a prospective cohort study in 500 patients

Abstract Background MR-proADM (mid-regional pro-adrenomedullin) is a stable pro-peptide of Adrenomedullin, which is expressed in various cell types such as heart, lung, and renal tissue. It is a prognostic parameter for heart failure (HF) and sepsis as well as all-cause and cardiovascular (CV) mortality. Purpose Considering the characteristics of MR-proADM as a reliable biomarker for adverse events, we aimed to investigate the prognostic impact of MR-proADM in patients undergoing elective cardiac surgery. Methods We prospectively enrolled patients undergoing elective cardiac bypass and/or valve surgery at the department of cardiac surgery between May 2013 and August 2018. Blood samples were taken one day prior to surgery. MR-proADM was measured using an automated immunofluorescence assay. Patients were followed prospectively until endpoints were reached. The primary endpoint was the composite of hospitalization for heart failure (HHF) or CV mortality, the secondary endpoint was postoperative atrial fibrillation (POAF). The multivariate regression model was adjusted for age, sex, NT-proBNP, type of surgery, and CRP-level at baseline. Results A total of 500 patients (146 female [29.2%]; median age 69.8 years [IQR 60.6-75.5]) were followed over a median of 4.6 years (IQR 3.0–5.8). Valve surgery was performed in 214 (42.8%) patients, 160 (32%) underwent a bypass operation and 126 (25.2%) a combined valve and bypass surgery. The median MR-proADM value of the entire study population was 0.58 nmol/L (IQR: 0.44-0.79 nmol/L). Patients were stratified in risk categories based on their MR-proADM values (Low Risk ≤0.63nmol/L, Intermediate Risk 0.63-0.83nmol/L, High Risk >0.84nmol/L). Patients in the highest category presented with higher rates of diabetes mellitus (p <0.001), COPD (p <0.001), HF (p=0.009) and either bypass surgery (p=0.039) or the combination of bypass and valve surgery (p=0.008), compared to patients in the lowest tertile. We observed a significant increase in 5-year’s event rates for HHF/ CV Mortality in patients in higher risk groups (Low Risk 8.6% vs High Risk 37.7%, p <0.001, Figure 1). The adjusted Cox regression model found that MR-pro ADM was independently associated with a risk increase for HHF/ CV Mortality (adjusted HR of 4.45, 95% CI 2.55-8.09; p<0.001, Figure 2) comparing the High Risk to the Low Risk Group. A comparable risk increase could be observed in POAF, with an adjusted HR of 2.61 (High Risk Group vs Low Risk Group, 95% CI 1.46-4.67, p<0.001). Conclusion Within the prospective investigation, MR-pro ADM was found to be an independent predictor for HHF and CV mortality in patients undergoing cardiac bypass and/or valve surgery. Furthermore, there was a consistent predictive potential for POAF. In the era of personalized medicine, preoperative MR-pro ADM levels could help to identify patients at risk for serious adverse events, in order to apply intensified secondary prevention and reduce mortality and morbidity.

Out-of-hospital cardiac arrest in patients with psoriasis

Abstract Background Psoriasis is a complex autoinflammatory disease that has been associated with atherosclerosis, higher risks of cardiovascular diseases, and electrocardiographic changes. Whether these risk factors lead to higher risks of out-of-hospital cardiac arrest (OHCA) is undetermined. Purpose To investigate whether psoriasis is associated with OHCA. Method Using the nationwide Danish Cardiac Arrest Registry, we identified adult (≥18 years) OHCA patients of presumed cardiac cause with and without psoriasis between June 1st 2001 and December 31st 2019. The association of cardiac arrest was estimated using time-varying Cox regression fitted with a nested case-control design where we matched up to five controls per case on age, sex and year of OHCA and 4 comorbidities: ischemic heart disease, congestive heart failure, cardiovascular risk factors, and major extra cardiac organ disease. In subgroup analyses, the main analysis was repeated in patients with severe psoriasis (presence of inpatient hospital contact during the previous year) as compared to mild psoriasis. Results We included 43,967 OHCA cases and matched with 219,772 controls from the general population. The median age was 72 years, 68% were male and 26% had ischemic heart disease, 21% had congestive heart failure, 57% had cardiovascular risk factors, and 33% had extra cardiac organ disease (Table 1). We identified 1,145 (2.6%) cases and 4,971 (2.3%) controls who had psoriasis. Compared with cardiac arrest cases without psoriasis, cases with psoriasis had similar age and sex distribution, prevalence of ischemic heart disease, and congestive heart failure, but a higher prevalence of cardiovascular risk factors, major extra cardiac organ disease and Charlson score distribution. Psoriasis was significantly associated with higher hazard ratios of OHCA: HR 1.16 [95% confidence interval: 1.08 - 1.23] (Figure 1). Compared to no psoriasis, having severe psoriasis was significantly associated with higher hazard of OHCA: HR 1.98 [95% confidence interval: 1.10 - 3.61], while mild psoriasis was not (Figure 1). Conclusion In this nationwide nested case-control study, psoriasis was significantly associated with increased hazard of out-of-hospital cardiac arrest. Furthermore, the association was only significant with severe psoriasis compared to those without psoriasis, while mild psoriasis was not. This study highlights the importance of examining cardiovascular risk factors and prioritizing prevention of cardiovascular disease in patients with psoriasis.Figure 1Table 1

Satisfactory self-rated health is associated with better clinical outcomes in patients with ST-segment elevation myocardial infarction

Abstract Background It is well known that health status is a risk factor for cardiovascular diseases, but its specific impact on the prognosis of patients with acute myocardial infarction remains unclear. Purpose This study was aimed to investigate the impact of varying health self-evaluation on the long-term outcomes of patients diagnosed with ST-elevation myocardial infarction (STEMI). Methods Data for this study were obtained from a retrospective cohort of patients admitted to and discharged from 72 secondary and tertiary hospital from 2010 to 2023. Patients were divided into satisfied group and dissatisfied group based on their responses to a self-assessment health questionnaire. Baseline data of the two groups were compared, and the relationship between health status and major cardiovascular and cerebrovascular adverse events (MACCE) was analyzed using multivariate cox regression. MACCE, defined as the composite endpoint of cardiac death, recurrent myocardial infarction, stroke and revascularization, was the primary endpoint, with each component considered a secondary endpoint. Results Among STEMI patients, 25214 patients reported satisfaction with their health, while 375 patients expressed dissatisfaction. The satisfied group exhibited a younger age, fewer females, a higher rate of primary percutaneous coronary intervention (PPCI) and PCI during hospitalization, a better Killips classification and a lower prevalence of concomitant disease such as diabetes, hypertension, chronic kidney disease, and cerebrovascular disease. After a median follow-up of 1626 days, the satisfied group demonstrated significantly lower proportions of total death, cardiac death, recurrent myocardial infarction and stroke compared to dissatisfied group. Multivariate COX regression showed that satisfactory health self-rating was associated with a decreased risk of MACCE (HR 0.813, 95%CI 0.704-0.939, P=0.005), stroke (HR 0.670, 95%CI 0.511-0.878, P=0.003), and recurrent myocardial infarction (HR 0.732, 95%CI 0.548-0.979, P=0.035). Conclusions Satisfactory self-rated health is associated with better clinical outcomes in STEMI patients.

High physical activity relates to higher risk of incident carotid plaque components

Abstract Background The rupture of carotid atherosclerotic plaque, primarily driven by plaque components, is among the leading causes of ischemic stroke. Although physical activity (PA) stands as a major modifiable target for prevention of atherosclerotic diseases, recent studies suggested a potential adverse impact of high-volume PA on atherosclerotic plaque burden in athletes. Data remains scarce from the community-dwelling population regarding to the impact of PA on the longitudinal change of carotid plaque components. Objectives To assess the association between PA and the incidence of carotid plaque components and explore whether the association of PA with stroke and all-cause mortality differs by the presence of plaque components. Methods Between 2007 and 2012, in a community- dwelling cohort in Netherlands, 1327 stroke-free persons (mean ± standard deviation age 72 ± 9 years, 45% women) with carotid atherosclerosis (carotid intima-media thickness > 2.5 mm) were invited for magnetic resonance imaging (MRI) to assess carotid plaque components. From these, 696 persons (1267 carotid arteries) underwent a follow-up MRI between 2014 and 2017 (median between-scan interval 6 years). Carotid plaque components included calcification, intraplaque hemorrhage (IPH), and lipid-rich necrotic core (LRNC). The volume of moderate, vigorous and total PA (unit: metabolic equivalent task hour, MET-h) was assessed using LASA Physical Activity Questionnaires around the time of the first MRI scan. Participants were followed for the occurrence of stroke or all-cause mortality until December 31, 2019. Generalized estimation equation and Cox regression models were used in the analyses, with adjustments for plaque size and other cardiovascular risk factors. Results Compared to lowest quintile PA group, participants in the highest quintile total PA group had a higher risk of new onset of plaque components, odds ratio (95%CI) 2.69 (1.21; 5.94) for calcification, 1.35 (0.82; 2.24) for LRNC and 1.93 (1.12; 3.34) for IPH (Figure 1). Similar associations were observed for vigorous PA but not for moderate PA. Over a median follow-up of 9.5 years, 118 persons suffered a stroke and 298 died. As shown in table 1, baseline IPH, rather than LRNC or calcification, modulated the associations of PA with stroke and all-cause mortality (P-interaction <0.05): higher total PA was associated with a lower risk of stroke among IPH-free persons, with the hazard ratio (95% CI) of 0.929 (0.867; 0.996) per 10 MET-h/week increase; no associations between PA and stroke were found among those with IPH. Similar associations were found between vigorous PA and all-cause mortality. Conclusions Among the middle-aged and elderly with subclinical atherosclerosis, high level PA, especially high vigorous PA, may lead to an unstable carotid plaque. The beneficial effect of PA on stroke and all-cause mortality is only among persons with a stable carotid plaque profile, especially without IPH.

Angiotensin-II receptor type 1 and endothelin-1 receptor type A agonistic autoantibodies in patients with STEMI: new kids on the block

Abstract Background The Prognosis after ST-elevation myocardial infarction (STEMI) remains poor. Angiotensin-II and endothelin-1 contribute to adverse prognosis after STEMI through molecular mechanisms that lead to myocardial inflammation, fibrosis and, ultimately, adverse myocardial remodeling. Functional autoantibodies against angiotensin II type 1 (AT1R-AAs) and endothelin-1 type A (ETAR-AAs) receptors bind to the same receptors as natural ligands, eliciting similar (and amplified) responses. In patients with STEMI, AT1R-AAs and ETAR-AAs have been associated with a higher risk of developing microvascular obstruction and left ventricular remodeling. Both microvascular obstruction and left ventricular remodeling are associated with a poor prognosis. Purpose To assess the prognostic role of AT1R-AAs and ETAR-AAs after STEMI. Methods Consecutive STEMI patients who underwent primary percutaneous coronary intervention within 12 h after pain onset were enrolled in this prospective study. The levels of AT1R-AAs and ETAR ETAR-AAs at the time of hospital admission were measured using an enzyme-linked immunosorbent assay (ELISA) in all patients. The incidence of major adverse cardiovascular events (MACE, defined as a composite of cardiovascular mortality, myocardial re-infarction, and hospitalizations for heart failure) during follow-up was the primary outcome. Autoantibody seropositivity was defined according to ELISA’s kit manufacturer’s instructions (levels > 10 U/mL). Results Two hundred patients with STEMI were enrolled. The baseline characteristics of the patients are shown in Table 1. Of these, 110 (55%) were seronegative for both autoantibodies, 44 (22%) were seropositive for one autoantibody (but not both), and 46 (23%) were seropositive for both autoantibodies. The incidence of MACE over a 14-month median follow-up was higher in patients with double (31%) and single (25%) seropositivity than in seronegative patients (13%, p=0.009 and p=0.06, respectively). Survival free from MACE was significantly different across the different degrees of autoantibody seropositivity (Figure 1). In the multivariable Cox regression analysis, adjusted for the variables that were significant in the univariate analysis (highlighted in bold in Table 1), double seropositivity was independently associated with an increased risk of MACE (hazard ratio 2.386, 95 % CI 1.471-3.864, p<0.001). Conclusions The degree of seropositivity for AT1R-AAs and ETAR-AAs is associated with an increased risk of MACE after STEMI. Our findings provide valuable mechanistic insights into the pathophysiology of STEMI and pave the way for future therapies focused on the improvement of long-term prognosis after acute coronary syndromes.

Lipoprotein(a) and cardiovascular prognosis of familial dyslipidemias: data from a 10-year follow-up study

Abstract Background Familial dyslipidemias, such as heterozygous familial hypercholesterolemia (FH) and familial combined hyperlipidemia (FCH) are associated with premature cardiovascular (CV) disease. On the other hand, increased lipoprotein(a) [Lp(a)] is considered as the most prevalent monogenic lipid disorder in the general population. Purpose This study aimed to longitudinally follow up two specific populations with familial dyslipidemias associated with increased CV risk, namely FH and FCH, and compare them with reference to their CV prognosis, investigating in parallel the effect of Lp(a) levels. Methods 433 patients with FH (34% males, mean age 44.2±12.8 years) and 476 patients with FCH (57% males, mean age 49.0±11.1 years) from the outpatient lipid clinic of our hospital, without history of CV disease, who fulfilled the FH and FCH criteria, respectively, participated in the study. Participants were evaluated for a mean follow-up period of 9.6±7.6 years, with at least one annual visit. Venous blood samples were obtained at baseline in all patients for the determination of lipid profile and levels of Lp(a). All subjects were on lipid-lowering medication during the follow-up period. The endpoint of our study was the composite of major CV events (coronary artery disease events and stroke). Results The incidence of the composite endpoint of major CV events during the follow-up period in the total population was 6.5%, while it was greater in patients with FH compared to patients with FCH (8.1% vs 5.5%, p=0.03). Regarding CV risk factors, FCH compared to FH patients had greater prevalence of baseline hypertension (36% vs 9.7%, p<0.001) and diabetes (11% vs 2%, p<0.001), whereas FH patients had greater Lp(a) levels (37.4±40.3 vs 29.7±34.6 mg/dl, p<0.01). Multiple Cox regression analysis revealed that FH patients had greater CV risk compared to FCH patients (HR 2.17, 95% CI 1.10-4.26, p=0.02). Moreover, in FH patients, increased baseline Lp(a) levels (≥30mg/dl) were an independent predictor of major adverse CV events (HR 2.37 95% CI 1.41-4.90, p=0.02), whereas in FCH patients increased Lp(a) was not an independent predictor. In FCH patients the presence of diabetes at baseline was a strong independent prognosticator of adverse CV events (HR 3.56 95% CI 1.19-11.33, p=0.03), after adjustment for confounding factors. Conclusions FH patients have greater CV risk compared to FCH patients. In FH patients, the presence of increased Lp(a) doubles the CV risk, beyond low density lipoprotein cholesterol levels. On the other hand, in FCH patients the presence of diabetes triples the CV risk, whereas Lp(a) does not convey an independent prognostic value.

Enhancing primary prevention: the incremental predictive value of high-sensitivity cardiac troponin T beyond ASCVD risk assessment

Abstract Background Atherosclerotic cardiovascular disease (ASCVD) is a global health challenge, prompting widespread use of conventional risk assessment tools (SCORE2 in Europe and the ASCVD Risk calculator in the United States) to guide preventive strategies. Emerging evidence indicates that high-sensitivity cardiac troponin (hsTn) may refine risk stratification. Objective We investigate whether measuring hsTnT in primary prevention correlates with mortality and enhances prediction compared to conventional risk score stratification. Methods Utilizing National Health and Nutrition Examination Survey (NHANES) data (1999 to 2004) linked to the National Death Index, our cohort included individuals without a history of CVD at baseline and suitable for assessment of the ASCVD ACC/AHA risk score. Individuals were grouped based on computed 10-year risk (low: <5%; borderline: 5-7.5%; intermediate: 7.5-20%; high: ≥ 20%). hsTroponin T levels were measured (Roche assay, 99 th percentile 22ng/L for men and 17ng/L for women). Cox regression estimated association between ASCVD risk categories, with or without hsTnT, and all-cause and cardiovascular mortality. Results Among 5257 adults, 47% male, mean age 54 ± 9.1 years, the mean 10-year ASCVD risk was 8.17 ± 8.2%, grouped as: low: 53.3%; borderline: 11.5%; intermediate: 23.9%; and high: 11.3%. hsTnT above the 99 th percentile was measured in 1.1%, 2.7%, 4.9% and 13.4%, respectively (p < 0.001). Over 16.2 ± 3.4 years, all-cause and cardiovascular death was 22.3% and 5.6%, respectively. Compared to low-risk, the hazard ratio (HR) for all-cause death increased to 2.85 (2.2-3.7), 5.6 (4.2-7.5), and 15.3 (11.7-19.9) for borderline, intermediate, and high-risk, respectively. A significant interaction with hsTnT above 99 th percentile was observed (low: HR 3.5 (1.3-9.2); borderline: HR 4.75 (2.1-10.8); intermediate: HR 2.6 (1.8-3.7), high: HR 2.2 (1.7-2.9), p<0.01 for all interactions, see Fig. 1). For cardiovascular death, a significant interaction occurred in intermediate (HR 3.3 (2-5.4), p<0.001) and high-risk (HR 3.6 (2.2-6), p<0.001) groups. Conclusion Our findings suggest that hsTnT provides incremental predictive value, at least doubling the hazard of all-cause death across all risk categories, and tripling the hazard of CV death in intermediate and high-risk groups, compared to ASCVD risk stratification alone. The integration of troponin measurements into risk assessment strategies could refine primary prevention approaches.

Peripheral artery disease, antithrombotic treatment and outcomes in European and Asian patients with atrial aibrillation: a report from 2 prospective observational registries

Abstract Background In patients with atrial fibrillation (AF), the impact of peripheral artery disease (PAD) on oral anticoagulant (OAC) therapy use and the risk of outcomes remains unclear. Objective To analyse the epidemiology of PAD in a large cohort of European and Asian AF patients, and the impact on treatment patterns and risks of adverse outcomes. Methods We analysed AF patients from two large prospective observational registries. We identified patients with PAD as reported by the investigators. Logistic regression analysis was used to assess factor associated with the presence of PAD at baseline. OAC prescription and risk of outcomes were analyzed according to the presence of PAD, using adjusted Logistic and Cox regression analyses. The primary outcome was the composite of all-cause death and major adverse cardiovascular events (MACEs). Interaction analyses were also performed according to different subgroups. Results 15,497 patients with AF (mean age 68.9, SD 11.6 years; 38.6% female, 30% from Asia) were included in the analysis. PAD was found in 941 patients (6.1%), with higher prevalence among European individuals compared to Asian (8.1% vs 1.2%, p<0.001). Patients with PAD were older, more likely with permanent AF, more symptomatic and with higher thromboembolic and bleeding risk. On logistic regression analysis, European patients had 6-fold higher odds of presenting with PAD compared with Asians (Figure 1, Panel A). Other comorbidities and increasing age were associated with higher odds of prevalent PAD (Figure 1 Panel A). Conversely, female sex was associated with lower odds of having PAD at baseline. With age modelled as a continuous variable, and odds of PAD at baseline, there was a non-linear relationship, with the odds of PAD increasing almost linearly until 70 years, plateauing afterwards (Figure 1 Panel B). After adjustments, PAD was associated with lower use of OAC (OR 0.69, 95% CI 0.57-0.85). On Cox regression analysis, PAD was associated with a higher risk of the primary composite outcome (HR 1.28, 95%CI: 1.08-1.52) and all-cause death (HR 1.40, 95%CI: 1.16-1.69). A significant interaction was observed between PAD and age, with greater risks of PAD found in younger patients (<65 years) for the primary outcome (pint=0.014, Figure 2, panel A). Consistent results were observed when we analysed the interaction between PAD and age, modelled as a restricted cubic spline, where the risk of the primary outcome followed a J-curve across age, while patients without PAD showed an approximately linear relationship (pint<0.001, Figure 2, Panel B). Conclusions In patients with AF, PAD is associated with lower use of OAC and higher risk of adverse outcomes, with a greater risk seen in younger patients.Figure 1Figure 2

Impact of coronary revascularization on clinical outcomes of post-acute myocardial infarction patients with left ventricular thrombus

Abstract Background Left ventricular thrombus (LVT) is an uncommon, but dangerous complication seen in post-acute myocardial infarction (AMI). With advances in percutaneous coronary intervention (PCI) techniques, the incidence of post-AMI LVT has declined in the contemporary era. However, a minority of patients do not undergo coronary revascularisation due to medical contraindications or patient preference. This study aimed to evaluate the clinical characteristics and outcomes of post-AMI LVT patients treated with and without coronary revascularisation. Methods This was a retrospective study of 263 consecutive post-AMI patients diagnosed with LVT from November 2012 to January 2021, retrieved from a echocardiography database. Patients were stratified by the presence or absence of revascularisation treatment. Baseline clinical characteristics, treatment and outcomes data were collected and analysed. Results The median follow-up duration was 2.9 years (IQR: 0.9 – 4.7). A majority of post-AMI LVT patients underwent revascularisation via PCI (71.5%, n = 188), CABG (4.2%, n = 11) or thrombolysis (0.4%, n = 1). Unrevascularised patients (24.0%, n = 63) were older (p <0.001), more likely to be female (p <0.001), and had more co-morbidities such as previous stroke (p <0.001), heart failure (p = 0.001), chronic kidney disease (p = 0.020), and malignancy (p = 0.021). More unrevascularised patient had NSTEMI (p < 0.001), and significantly fewer were treated with triple therapy (p < 0.001). Incidence of LVT resolution was lower (p < 0.001) while all-cause mortality was higher (p < 0.001) for unrevascularised patients on univariate survival analyses. On multivariable Cox regression, revascularisation status was not an independent predictor of LVT resolution, bleeding, stroke, or all-cause mortality outcomes. Conclusion While unrevascularised post-AMI LVT patients had poorer outcomes compared to revascularised patients overall, revascularisation status itself was not independently associated with poorer clinical outcomes. Optimising medical therapy such as triple therapy remains a key treatment goal for post-AMI LVT patients.

Mini nutritional assessment is a predictor of mortality and morbidity in patients with pulmonary arterial hypertension

Abstract Background Malnutrition has been demonstrated as a predictor for unfavorable clinical outcomes in chronic heart failure, and may affect patients with pulmonary arterial hypertension (PAH). The Mini Nutritional Assessment (MNA) is a reliable indicator for nutritional status assessment, but its relationship with mortality risk and hospitalization in PAH patients has not yet been investigated. Purpose The study aimed to determine whether the MNA has prognostic value in stable patients with PAH. Methods A prospective multicenter study was performed. All patients completed the MNA at study entry in outpatient clinic or during planned hospitalization. The primary endpoint was all-cause mortality. Secondary end-point was the composite end-point of all cause death or PAH-related hospitalizations. Patients with malnutrition (MNA ≤17 points) or at risk of malnutrition (MNA 18-23,5 points) were considered as having abnormal nutritional status for statistical analysis. Results 182 PAH patients were included to the study (mean age 60 ± 17 years; 73% females; 57% idiopathic PAH). Abnormal nutritional status was identified in 68 (37%) patients. Median and the range of follow up period was 23 months and 0–32 months, respectively. 34 (18.7%) patients died, 53 (29.1%) were hospitalized due to PH, and 57 (31.3%) achieved the composite secondary end-point. Kaplan-Meier survival curves revealed significant differences in overall survival between patients with abnormal MNA and normal MNA, p <0.0001, and significant differences in composite risk of death and PAH-related hospitalization, p=0.02. In the multivariate Cox regression analysis including age, sex, and main risk factors (COMPERA 2.0 score, TAPSE/PASP, right atrial pressure, cardiac index, mix oxygen saturation), abnormal MNA remained significantly associated with all-cause mortality (HR 2.86 [95%CI: 1.29–6.38], p=0.01) and the composite end-point HR 2.39 [95% CI: 1.05–5.42], p=0.04) in PAH patients. Conclusions Using MNA as a routine screening tool allowed the detection of abnormal nutritional status in more than one third of PAH patients. Nutritional status assessed by the MNA was an independent predictor of all-cause death and the composite end-point of all-cause death and PAH-related hospitalization in patients with PAH.

Treatment of kidney disease: an analytical decision model at a Swiss university hospital

Abstract Background An observational hospital-based cohort study, where the kidney disease staging is identified as a digital marker, and the association between the standardised staging of Kidney Disease (KD) and the outcomes is assessed along the treatment process. Methods The clinical and administrative data for all patients are stored in the Clinical Data Warehouse. A specific digital marker for an exact KD staging is applied. Three retrospective patient cohorts for exact and imprecise staging and missing diagnosis are defined and compared regarding the in-hospital mortality, all-cause mortality and disease progression. Results In total, 83146 hospitalisations of 40421 patients with KD, treated in 2014-2023 (2016-2023 will be updated) were identified; the number of the first hospitalisations with exact staging was 847 (2%), unprecise 29934 (72%) and missing diagnosis (26%). The demographic and baseline factors distribution between groups was tested with no association (chi-squared test statistic). The median survival time with a 95% CI was 7.94 (7.66, 8.81) years for the exact and 7.47 (7.42, 7.53) for the imprecise staging group. A log-rank and loglikelihood tests indicated a significant difference in survival between the groups, p < 0.0001. The Cox regression model shows a statistically significant difference in Hazard Ratio; KD staging, age, Elixhauser van Walraven index, treatment, nephrotoxic medication, contrast agent application, and AKI were identified as the significant covariates, C-statistic 0.730, Likelihood ratio test, Wald test, log-rank score on 42 df, p < 2e-16. ANOVA analysis confirmed a significant difference in cost distribution between the groups. An economic decision model proposal integrates the findings, combining a profile-level Markov cohort with a Discreet Time-To-Event Simulation DICE. Conclusions The study demonstrates a better outcome regarding all-cause mortality, in-hospital mortality, and costs if a standardised KD staging was applied. Key messages • Intuition (clinical judgement) and standardised kidney disease staging perform differently regarding clinical outcomes and costs. • The study demonstrates a better outcome regarding all-cause mortality, in-hospital mortality, and costs if a standardised KD staging was applied.

Prior fecal immunochemical test positivity is associated with adverse prognosis in patients with acute ST-segment elevation myocardial infarction

Abstract Backgrounds While fecal immunochemical testing (FIT) is commonly used for disease screening, its significance in other conditions, particularly in patients with ST-segment elevation myocardial infarction (STEMI), is not extensively researched. Purpose This study aimed to investigate the impact of prior positive FIT results on the clinical prognosis of patients with STEMI. Methods The data for this study were derived from the Health and Medical Big Data Superplatform, comprising a retrospective cohort of patients discharged from 72 hospitals from 2010 to 2023. A total of 76,157 patients with acute STEMI patients were enrolled. Positive FIT was defined as "+-" or higher on the fecal occult blood test. Propensity score matching (PSM) was employed to balance differences between the two groups. Kaplan-Meier analysis with log-rank tests compared endpoint risks between groups, and a multivariable Cox regression model adjusted for potential confounders. The primary endpoint was Net Adverse Clinical Event (NACE), including cardiac death, recurrent myocardial infarction, revascularization, stroke, cerebral hemorrhage, and gastrointestinal bleeding. Results After 1:3 PSM,2,148acute STEMI patients were included, with 537 having prior positive FIT and 1,611 without. Patients with prior positive FIT were more likely to have comorbidities such as hyperlipidemia, prior malignancy, post-coronary artery bypass grafting, renal insufficiency, and prior cerebral hemorrhage. The prior positive FIT group had a higher proportion of prior clopidogrel and indobufen usage, while aspirin use during follow-up was lower. Kaplan-Meier analysis demonstrated a significantly higher risk of NACE in acute STEMI patients with prior positive FIT (before PSM: log-rank P = 0.001, after PSM: log-rank P = 0.005, Figure 1）, as well as increased rates of Major Adverse Cardiac and Cerebral Events (MACCE), all-cause death, and gastrointestinal bleeding (log-rank P < 0.05 for all). Multivariate Cox-proportional hazard analysis adjusted for age, sex, percutaneous coronary intervention during hospitalization, diabetes, hypertension, ischemic stroke, atrial fibrillation, medication during hospitalization, and follow-up showed similar results (Figure 2). Conclusions This study reveals a significant association between prior positive FIT and higher rates of NACE, MACCE, all-cause death, and gastrointestinal bleeding in STEMI patients within 1 year. A history of positive FIT results could serve as a prognostic indicator in this specific patient population.

Free fatty acids and mortality among adults in the United States: a report from US National Health and Nutrition Examination Survey (NHANES)

Abstract Introduction Free fatty acids (FFAs) serve as vital energy sources in multiple body tissues and they have been associated with elevated cardiovascular disease risk and mortality. There is a scarcity of prospective studies examining the associations between specific FFAs and long-term health outcomes. Purpose To examine the correlation between different FFAs types and all-cause or cardiovascular mortality in a large, nationally representative sample of adults in the United States (US), and examine how different concentrations and types of FFAs may mediate this association. Methods This cohort study included 3719 and 3900 participants in the unsaturated fatty acids (USFAs) and saturated fatty acids (SFAs) populations, respectively, who participated in the US National Health and Nutrition Examination Survey (NHANES) from 2011-2014. Multiple model calibration was performed using univariate and multivariate cox regression analysis to explore the associations between circulating FFAs and all-cause or cardiovascular mortality. Results The UFAs (myristoleic acid (14:1 n-5), palmitoleic acid (16:1 n-7), cis-vaccenic acid (18:1 n-7), nervonic acid (24:1 n-9), eicosatrienoic acid (20:3 n-9), docosatetraenoic acid (22:4 n-6), and docosapentaenoic acid (22:5 n-6)) were associated with an elevated risk of all-cause mortality ((hazard ratio (HR) 1.02 [1.006-1.034]; P=0.004), (HR 1.001 [1.001–1.002]; P＜ 0.001), (HR 1.006 [1.003–1.009]; P＜ 0.001), (HR 1.007 [1.002–1.012]; P = 0.003), (HR 1.027 [1.009–1.046]; P= 0.003), (HR 1.024 [1.012–1.036]; P＜ 0.001) and (HR 1.019 [1.006–1.032]; P = 0.005), respectively), whereas docosahexaenoic acid (22:6 n-3) was linked to a lower risk (HR 0.998 [0.996–0.999]; P = 0.007). Among SFAs, palmitic acid 16:0 was associated with a higher all-cause risk (HR 1.00 [1.00–1.00]; P = 0.022), while tricosanoic acid (23:0) and lignoceric acid (24:0) were associated with lower risks (HR 0.975 [0.959–0.991]; P = 0.002) and (HR 0.992 [0.984–0.999]; P = 0.036). Kaplan–Meier survival curves according to FFAs quartiles shown the highest risk for all-cause mortality was observed in the group with the highest concentration, except serum 23:0. The association between FFAs concentration and cardiovascular mortality in the multivariate analysis indicated that only 22:6 n-3 (HR 0.997 [0.994-1.000]; P=0.035) had a lower risk of cardiovascular mortality in the USFAs group, while none of the SFAs was found to be associated with cardiovascular mortality. While, the relationship between 22:6 n-3, and cardiovascular mortality was characterized by neither a linear nor nonlinear association (P-linear = 0.215; P-nonlinear = 0.260). Conclusion In this cohort of US adults, the types and concentrations of FFAs exhibited significant associations with risk of all-cause mortality. Achieving optimal concentrations of specific FFAs effectively lowered this risk of all-cause mortality, but this benefit was not observed in regards to cardiovascular mortality.FFA and all-cause mortality

Continuation of beta-blockers at discharge is associated with improved outcome in patients with HFpEF and concomitant moderate aortic stenosis

Abstract Background In patients with severe aortic stenosis or decompensated heart failure with preserved ejection fraction (HFpEF), beta-blockers are usually discontinued despite the absence of unequivocal evidence. The data on the effect of beta-blockers in patients with moderate aortic stenosis (MAS) are scarce. Aim To investigate the relationship between beta-blocker use and outcome in patients with MAS, who were hospitalized for decompensated HFpEF. Methods The current study includes 61 patients admitted for decompensated HFpEF with concomitant MAS. The mean age of the population was 82.7±7.59 years old and 41% were females. The diagnosis MAS was established on criteria including aortic valve area between 1-1.5 cm², mean gradient - 20-39 mmHg, and max velocity between 3-3.9 m/s. For those with borderline measurements, the Doppler Velocity Index (DVI) was calculated (DVI < 0.25 indicates severe aortic stenosis). All echocardiographic data were assessed by an experienced echocardiographer. Patients with previous aortic valve replacement and a severe mixed of multivalvular disease were excluded. Result The median follow-up was 52 months (interquartile range 34-63 months). During this period 38 patients (62.3%) died from any cause while 42 (68.9%) individuals experienced a composite endpoint, of all-cause death or hospitalization due to worsening HFpEF. In survivors, we observed higher prescription of beta-blockers at hospital discharge (66% vs. 34%, p<0,05) and better diastolic function than in patients with endpoints. In multivariate Cox regression analysis the use of beta-blockers (HR = 0,27; 95% CI 0,13-0,57; p<0.01) and better diastolic function, defined as higher septal e` (HR=0,76; 95% CI 0,61-0,94; p=0.01) were identified as independent predictors for both - survival and composite endpoint (Figure 1). Advanced age was recognized as an associated factor for outcomes. Conclusion In the present study, continuation of beta-blockers at discharge was independently associated with better survival in patients with decompensated HFpEF and concomitant MAS. It remains to be addressed in future studies, whether or not beta-blockers should be started in these patients or if there is any prognostic interaction between beta-blockers and aortic valve intervention for MAS.Figure 1.Kaplan-Meier survival curve