Cox Regression Model Research Articles

Role of urea to creatinine ratio in the prediction of outcomes in chronic heart failure

Abstract Background Renal function predicts events in chronic heart failure (HF). Urea to creatinine ratio (UCR) is a simple and cheap biomarker which correlates with neuroendocrine pathways. Objectives Evaluate the prognostic role of UCR in patients with chronic HF. Methodology 86 patients with chronic HF from an academic hospital were included (with reduced, mildly reduced or improved left ventricular ejection fraction). UCR was calculated at baseline, and patients were followed for a median of 360 (interquartile range 180-472) days. We plotted ROC curves for NT-proBNP and UCR and evaluated two scenarios using the Kaplan-Meier curve to determine the event-free survival. We grouped patients into four subgroups: a) UCR and NT-proBNP below the cut-off; b) UCR above and NT-proBNP below; c) UCR below and NT-proBNP above; and d) both above the cut-off. A second scenario was analysed, grouped as follows: a) UCR and NT-proBNP below; b) at least one of them above the cut-off; and c) both above the cutoff. The primary endpoint was cardiovascular death or HF hospitalisation. The level of significance was 5%. Results The mean age was 66.1±12.1y, and 60.5% were male. There were 28 events in the follow-up (32.5%). The ROC curve for UCR had an AUC of 0.75 (CI 0.64-0.86; p=0.0002) for a cut-off of 43.8 (sensitivity of 75% and specificity of 70.7%). The AUC for NT-proBNP was 0.64 (0.51-0.77; p=0.043) for a cut-off of 2010 pg/mL (sensitivity of 64.3% and specificity of 65.5%). In the Cox regression model, the UCR was the only independent predictor with HR of 1.06 per 1 unit increase (1.03-1.10; p=0.0002). UCR above cut-off (as a categorical variable) was the only independent predictor, with HR 5.34 (2.26-12.6; p=0.0001). Kaplan-Meier curves in Figures 1 and 2 show the UCR performance associated with NT-proBNP. Conclusions UCR is a simple and cheap biomarker that has been shown to have predictive power, probably due to persistent neuroendocrine activation in patients with low volume. In this population, elevated UCR added risk even in patients with low levels of NT-proBNP.

High ABCD2-score after transient ischemic attack is associated with a two-fold higher stroke-rate during long-term follow-up

Abstract Background The ABCD2-score is a validated risk score used to estimate the short-term risk of stroke after transient ischemic attack (TIA). However, "real-world" contemporary data on the long-term risk of stroke after TIA according to ABCD2-score are needed in order to guide preventive strategies. Purpose To determine the long-term risk of stroke after TIA according to modified ABCD2-score (high-risk (≥4 points) versus low-risk (<4 points)). Methods Patients aged ≥18 years with first-time TIA were included from the Danish Stroke Registry (2014-2020). The study population was stratified in high-risk (≥4 points) and low-risk (<4 points) ABCD2-score group. We utilized a modified ABCD2-score consisting of the following parameters: age ≥60 years, hypertension, clinical features, and diabetes. The 3-year risk of ischemic stroke and all-cause mortality was compared between the high-risk and low-risk group using the Aalen-Johansen and Kaplan-Meier estimator. A cox regression model was also conducted. Results In total, 21,433 patients with first-time TIA were included; 1,281 (6.0%) in the high-risk and 20,152 (94.0%) in the low-risk group. Patients in the high-risk group were older (77.5 years [interquartile range [IQR] 70.8-84.1] versus 70.3 years [IQR 60.1-78.2]), more often females (52.2% versus 46.6%) (p <0.001), more comorbid and received more medication compared with the low-risk group at baseline. The 3-year cumulative incidence of stroke was 6.0% [95% CI: 4.6-7.5] in the high-risk group and 4.2% [95% CI: 3.9-4.5] in the low-risk group, and the unadjusted hazard ratio (HR) was 1.6 (95% CI 1.2 – 2.0) (Figure 1). The cumulative incidence of all-cause mortality within three-years after TIA was 28.9% [95% CI: 26.1-31.7] in the high-risk group and 10.3% [95% CI: 9.9-10.8] in the low-risk group. The unadjusted HR was 3.2 (95% CI 2.8 – 3.6). Conclusions Patients with high-risk ABCD2-scores had an almost two-fold higher associated long-term stroke-rate compared to those with low-risk scores. Trials focusing on preventive measures, including evidence-based antithrombotic strategies, especially for the high-risk group are warranted.

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

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.

Are early emotional and behavioral problems related to subsequent asthma in preschool children?

Abstract Background The most common mental health problems in preschool children are emotional and behavioral problems, and one of the most common chronic inflammatory diseases in children is asthma. Most research on the relationship between emotional and behavioral problems and asthma includes school-aged children. The current study aimed to explore the association between emotional and behavioral problems during preschool years and the risk of asthma in a Swedish context. Methods The study was a longitudinal cohort study, with 6954 children aged 3-5 years for which data on emotional and behavioral problems through the Strengths and Difficulties Questionnaire were collected in Uppsala Region, Sweden, between 2013 and 2017. The cohort was followed with data from the National Patient Register from 2013 to 2022. Asthma was defined as having at least three diagnoses (ICD-10 codes: J45-J46) during follow-up. Unadjusted and adjusted cox regression models were used to analyze data. Results A total of 269 children (3.9%) had diagnosed asthma during follow-up. Preliminary results show that children with emotional symptoms, rated separately by mothers (HR: 1.62, 95% CI: 1.20-2.20), fathers (HR: 1.49, 95% CI: 1.10-2.03), and preschool teachers (HR: 1.53, 95% CI: 1.08-2.16) had increased risk of being diagnosed with asthma according to unadjusted cox-regression models. In addition, children with total emotional and behavioural problems, rated by fathers (HR: 1.51 95% CI: 1.10-2.07) were also at higher risk of being diagnosed with asthma. These associations remained significant when adjusting for background and sociodemographic factors. Conclusions Our findings point to the significance of a clinical awareness of the relation between emotional and behavioral problems and asthma in young children. Our findings highlight the importance of also considering somatic problems, including asthma, in children with early signs of emotional and behavioral problems. Key messages • Emotional and behavioral problems in preschool children is related to being diagnosed with asthma. • Somatic problems, as asthma, needs to be considered in children with emotional and behavioral problems.

Effects of prognostic nutritional index and obesity on 1-year mortality in patients with acute heart failure

Abstract Background Increased body mass index (BMI) has paradoxically been linked to improved survival rates among patients with acute heart failure (AHF). However, the impact of different nutritional statuses on this obesity paradox on 1-year mortality remains unclear. The prognostic nutritional index (PNI) is a simple tool to assess nutrition status. Recently, landmark findings such as the STEP-HFpEF (Semaglutide Treatment Effect in People With Obesity and HFpEF) trial showed at 1-year, semaglutide not only reduced weight considerably, but also significantly improved health-related quality of life, functional status, and CRP levels. Also, the semaglutide effects on heart disease and stroke in patients with overweight or obesity (SELECT) trial demonstrated a 20% reduction in cardiovascular outcomes. Purpose To investigate the association between obesity and AHF on all-cause mortality according to nutritional status. Methods The cohort study comprised 7258 patients with a cardiopulmonary condition, all of whom were admitted and included on-site at the Emergency Department (ED) in a large University Hospital in Denmark, between March 2020 and March 2022. The follow-up time was at least 365 days. 408 patients with AHF were identified by chart review by trained cardiologists for analysis. PNI was calculated according to the formula: 10×serum albumin (g/ dL) + 5×total lymphocyte count×109/L. A value ≥ 38 is considered well-nourished, and a value < 38 is considered malnourished. Patients were divided into High-PNI (≥38) and Low-PNI (<38) according to cut-off value of PNI. The Kaplan-Meier (KM) curves were used to analyze cumulative survival in each subgroup, and the log-rank test was used to compare differences between groups. Cox regression models were used to analyze associa­tions between BMI, nutritional status and outcomes, expressed as hazard ratios (HR) and relative 95% confi­dence intervals (CI). Results Amongst 408 hospitalized AHF patients, 384 (mean age 75.6 ±11.7) with available PNI scores were enrolled into this study. 55.7% (n=214) were male, 56.4% (n=93) died in the Low-PNI group and 34.2% (n=75) died in the High-PNI group within 1 year. After adjusting for potential confounders in the High-PNI population, compared with the under/normal and overweight BMI group, obesity was negatively associated with 1-year mortality, with adjusted HR of 0.47, 95% CI (0.24–0.94), P = 0.033. However, this correlation disappeared in the Low-PNI group (obese BMI: HR 1.2, 95% CI 0.71–2.1, P = 0.457). In addition, those who were overweight in the Low-PNI group had an 80% increase in 1-year risk of death. Conclusion Obesity (BMI>30) was associated with reduced 1-year mortality only in AHF-patients with good nutritional status. However, this association disappeared in malnourished patients. Consequently, additional research is essential to formulate weight loss recommendations for malnourished obese patients with AHF.

Ethnic disparity in the care and management of non-ST-segment elevation myocardial infarction and its impact on short-term and long-term survival: a long-term study of a national registry

Abstract Background Previous examination of data from the United Kingdom indicates no apparent ethnic disparity in the treatment of patients hospitalised with non-ST-segment elevation myocardial infarction (NSTEMI). However, it remains uncertain whether this lack of disparity results in similar long-term survival outcomes among ethnic minority groups, particularly those with multiple underlying risk factors for coronary artery disease, when compared to White patients. Purpose To assess the impact of quality of care on short-term and long-term survival among NSTEMI patients while examining disparities based on ethnicity. Methods We analysed records of 252,964 individuals diagnosed with NSTEMI from the Myocardial Ischaemia National Audit Project database spanning 2005 to 2019, alongside Office of National Statistics data for mortality. Among them, 233,158 were identified as White patients, while 19,806 were categorised as belonging to ethnic minority groups (Asian, Black, and mixed ethnicity). Propensity score matching was used to compare average treatment effects between cohorts while survival was compared using Cox regression model. Results Ethnic minorities were younger (median age in years) (66 vs. 73, P < 0.001), predominantly male (70% vs. 63%, P < 0.001), and exhibited a higher prevalence of cardiovascular risk factors such as diabetes (52% vs. 24%, P < 0.001), hypertension (67% vs. 54%, P < 0.001), hypercholesterolemia (49% vs. 34%, P < 0.001), and chronic renal dysfunction (13% vs. 8%, P < 0.001). Ethnic minorities more frequently underwent invasive coronary angiography (80% vs. 68%, P < 0.001), percutaneous coronary intervention (53% vs. 44%, P < 0.001), and coronary artery bypass grafting (5% vs. 4%, P < 0.001). After conducting propensity score matching, both cohorts had no significant differences in in-hospital all-cause mortality [odds ratio (OR) 1.13, confidence interval (CI) 0.89 – 1.43; P = 0.268], cardiac mortality (OR 1.20, CI 0.89 – 1.54; P = 0.209), one-year mortality (OR 1.01, CI 0.89 – 1.13; P = 0.893) and major adverse cardiovascular events (OR 1.21, CI 0.95 – 1.48; P = 0.108). However, upon conducting a five-year survival analysis, ethnic minorities had better survival rates than their White counterparts (Hazard ratio (HR) 0.89, CI 0.86-0.92; P < 0.001). Conclusions Despite ethnic minorities being at a higher risk for coronary artery disease, our findings indicate that they experience better five-year survival rates than White patients. This suggests equitable access to care and potentially a more aggressive treatment approach in this relatively young patient cohort.

Prognostic role of inflammatory status in type 2 myocardial infarction

Abstract Background there is a wealth of evidence on the importance of inflammatory status in destabilization of chronic artery plaques that led to acute myocardial infarction. However, its role in the setting of type 2 myocardial infarction (T2MI) is not yet specifically known. Purpose We investigated prognostic role of inflammatory parameters in T2MI. Methods We consecutively enrolled 461 T2MI patients from January 2017 to June 2021. T2MI was defined according to the fourth Universal Definition of Myocardial Infarction. We divided the overall population in patients who experience major cardiovascular events (MACE), n=166, and in those who do not (n=277). Receiver operating characteristic (ROC) curve analysis were used to assess the diagnostic accuracy of various inflammatory parameters for predict MACE occurrence during long term follow-up. We divided patients into two groups (high and low inflammatory burden) based on the value associated with the highest Youen index. Cox proportional hazards regression models were constructed to estimate the independent role of these parameters in predict MACE. Results We found that patients who experienced MACE had a higher level of inflammatory parameters, in particular hs-CRP (2.21±3.7 vs 1.48 ±3.5, p<0.001) and platelet-to-neutrophil ratio (3.72 ±1.52 vs 3.7±1.43, p=0.02). Using ROC analysis, the area under the curve (AUC) of hs-CRP was the largest among all inflammatory parameters and the optimal threshold, according to Youden’s index, was found to be 1.2 mg/dL. MACE-free survival curves, comparing groups with low hs-CRP (< 1.2 mg/dL) and high hs-CRP (≥ 1.2 mg/dL), showed that high hs-CRP was associated with a worse prognosis (p<0.001). At Cox regression models, hs-CRP value ≥1.2 mg/dL was independently associated with MACE (p=0.01) together with diabetes (p=0.006), chronic obstructive pulmonary disease (p=0.006), previous stroke (p=0.001) and older age (p<0.001). Conclusion T2MI patients who experienced MACE exhibited higher levels of inflammatory parameters. Patients with hs-CRP levels ≥1.2 mg/dL had a worse prognosis, independently predicting MACE. These findings underscore the potential utility of hs-CRP as a prognostic biomarker in risk-stratifying patients with T2MI and highlight the importance of addressing inflammatory status in optimizing patient management and improving outcomes.

Prognostic Evaluation of Conversion Therapy Following Hepatic Arterial Infusion Chemotherapy or Immunotherapy in Patients with Advanced or Transarterial Chemoembolization Unsuitable Intermediate-Stage Hepatocellular Carcinoma-A retrospective cohort study.

Patients with advanced-stage or intermediate-stage hepatocellular carcinoma (HCC) unsuitable for transarterial chemoembolization (TACE) had poor prognoses. Recent advancements in hepatic arterial infusion chemotherapy (HAIC) and immune checkpoint inhibitors (ICIs) have demonstrated higher tumor response rates, which improved overall survival (OS). HAIC achieves an OS rate of approximately 14.5-15.3 months with a 39.1-42.5% tumor response rate. In comparison, ICIs have a 12-14 month OS rate with a 26-33% tumor response rate. Given these promising responses, this study evaluates the efficacy of conversion therapy with curative intent following HAIC or ICIs, focusing on survival outcomes. We retrospectively analyzed 80 patients with advanced or TACE-unsuitable intermediate HCC. Patients completed two HAIC or four ICI cycles, followed by Response Evaluation Criteria in Solid Tumors (RECIST) criteria imaging. Based on demographics, cirrhosis status, Barcelona Clinic Liver Cancer classification (BCLC) stage, treatment responses, and treatment modality, survival impacts were analyzed. OS was compared between HAIC and immunotherapy groups. The effect of conversion therapy with curative intent on survival outcomes was analyzed using a Cox regression model. Among the 80 patients, 26 achieved positive response (CR/PR) with HAIC or ICIs, and 9 of them subsequently underwent conversion therapy with curative intent. Key prognostic factors included Child-Pugh stage B vs. A (HR=2.21, p=0.041), BCLC stage C vs. B (HR=4.38, p=0.011), and elevated AFP levels (HR=5.02, p<0.001). Positive responders saw substantial survival benefits (HR=0.26, p=0.001). Patients undergoing conversion therapy exhibited significantly enhanced survival. Median OS was 13.58 months with standard therapy, while the curative intent surgery group did not reach the median OS (p=0.002). For CR/PR patients, 48-month survival was 75.0% for the curative surgery group versus 38.0% for standard treatment. Conversion therapy with curative intent following HAIC or ICIs might enhances survival in patients with advanced or TACE-unsuitable intermediate-stage HCC.

Urinary artificial sweeteners and breast cancer risk in women from the Moli-sani Study

Abstract Background Artificial sweeteners (AS) are chemical substances developed by the food industry to reduce sugar and calories while maintaining sweetness. Cohort studies suggested an increased risk of certain cancers, including breast cancer (BC), associated with AS intake, however evidence exclusively relied on self-reported dietary data rather than objectively measured AS. We examined the association of urinary biomarkers denoting AS intake with BC risk in women from the large Moli-sani Study. Methods Using a case-cohort design, a sample of 987 middle-aged women (mean age 55±12 y) was randomly selected as sub-cohort and compared with 273 women with incident BC (26 of them also belong to the sub-cohort). A total of 6 commonly used AS (i.e. aspartame, acesulfame, saccharine, sucralose, cyclamate, and steviol glycosides) were measured through liquid chromatography-mass spectrometry in urinary samples (creatinine-adjusted concentrations; µg/mg) collected at baseline (2005-2010). The multivariable hazard ratios (HRs) were estimated through Cox regression models using the Prentice method, where each AS was dichotomized as absence/presence, independent of concentrations. Results The main urinary AS was saccharine (E954), contributing to 71% of total AS, followed by steviol glycosides (E960;11%). During a median follow-up of 13.2 y we identified 38 premenopausal and 235 postmenopausal incident BC cases. In multivariable-adjusted Cox analyses, none of the individual AS was associated with overall BC risk, nor was the total urinary AS (HR = 0.93; 95%CI 0.63-1.37 for 1-unit increment). Compared to absence, presence of sucralose (E955) in urine was linked to premenopausal BC (HR = 4.23: 95%CI 1.23-14.51; p = 0.022). Conclusions Urinary artificial sweeteners were not associated with BC risk. However, sucralose presence in urine was linked to a higher risk of premenopausal BC. Prospective, dose-related studies with larger sample size are warranted to possibly confirm our findings. Key messages • The presence in the urine of commonly used artificial sweeteners was not associated with breast cancer risk. • Presence of urinary sucralose was linked to higher risk of premenopausal breast cancer.

Lipoprotein (a), coronary artery disease risk, and MACE in individuals without standard modifiable risk factors in the UK Biobank

Abstract Background A significant proportion of patients with coronary artery disease (CAD) lack standard modifiable risk factors (SMuRFs; smoking, hypercholesterolaemia, diabetes and hypertension), for example with recent analyses demonstrating that around 25% of patients with ST-elevation myocardial infarction are SMuRF-less(1). With continued focus on primary prevention in cardiovascular disease, the SMuRF-less subset is likely to increase over time. A body of evidence has implicated lipoprotein (a) in CAD, but no such studies have investigated this association in a purely SMuRF-less population. Purpose To investigate the role of lipoprotein (a) in predicting CAD risk and major adverse cardiovascular events (MACE) in a large, SMuRF-less cohort. Methods The UK Biobank is a large prospective multicentre study which recruited over 500,000 participants in the UK aged 37-73 years at entry between 2006-2010. SMuRFs were defined as 1) smoking (current or historical), 2) hypercholesterolaemia – lipid lowering medication on enrolment or total cholesterol >5.5mmol/L or LDL-C >3.5mmol/L, 3) previous diagnosis of diabetes mellitus, or HbA1c >48mmol/mol, 4) previous diagnosis of hypertension. MACE was defined as a composite of coronary artery disease – previous myocardial infarction, percutaneous coronary intervention or coronary artery bypass graft surgery –, stroke, or all-cause mortality. Results Of the total UK Biobank cohort, 46,139 participants were identified as SMuRF-less together with a valid lipoprotein (a) level. Median follow-up duration was 12yrs. In univariate analyses (Table 1), there was no significant difference in lipoprotein (a) concentrations between individuals with and without MACE (16.9 vs. 17.1nmol/L respectively, p = 0.913). The overall event rate was low, with just 3% MACE (1381 events) overall. Older age, male gender, apolipoprotein A, apolipoprotein B, HbA1c level, HDL cholesterol level and body mass index were all associated with MACE. In regard to all-cause mortality alone, there was no association with lipoprotein (a) level, although the other aforementioned parameters were all significantly associated with this outcome. Similarly, lipoprotein (a) was not a significant predictor of stroke. However, there was a large difference in lipoprotein (a) levels between patients with and without CAD (27.2 vs. 17.1nmol/L respectively, p = 0.004). In Kaplan-Meier analysis, lipoprotein (a) level above the 77th percentile (60.3nmol/L) was significantly associated with CAD (p=0.032). In Cox regression models, despite the low event rate, lipoprotein (a) was a significant predictor of CAD (HR 1.00-1.01, p=0.01), and importantly the only potentially modifiable parameter (N = 39,433, 111 events, Table 2). Conclusion Lipoprotein (a) independently predicts CAD in those without SMuRFs, highlighting the importance of checking this parameter in such patients, particularly given the novel antisense technologies in development which may lower lipoprotein (a)(2).Univariate analysesCox regression for CAD

Investigating the influence of possible liver fibrosis on mortality in patients with coronary artery disease - a post-hoc ISCHEMIA trial analysis

Abstract Background There is a plethora of studies demonstrating that comorbidities (e.g., diabetes and renal dysfunction) directly influence outcomes in patients undergoing PCI or CABG for coronary artery disease (CAD). Yet, liver dysfunction is not really included in current risk assessment beyond the presence of liver cirrhosis. Retrospective single center evidence now suggests that the presence of liver fibrosis may be an indicator of elevated risk. Using the FIB-4 score, where increasing values correlate with increaseing degrees of histological liver fibrosis, liver fibrosis could already be detected with all required laboratory values (AST, ALT, platelets) within normal range. In addition, the study suggests a beneficial effect of off-pump CABG when FIB-4 is elevated. This finding contradicts current randomized evidence, negating any difference between off and on-pump CABG. Since randomized trials always suffer from strong selection of low risk patients, it is conceivable that trial patients may primarily have low FIB-4 scores. Purpose To address the distribution of FIB-4 scores in a selected trial population with CAD (from the ISCHEMIA trial) and relate the degree of liver fibrosis reflected by the score to mortality. Methods The FIB-4 score was calculated for all patients. According to the standard classification, a value of greater than 1.2 reflects a 90% chance of the presence of histological liver fibrosis. The imapct of FIB-4 on late all-cause mortality was assessed as a continuous and categorical variable using maximally selected rank statistics determined FIB-4 cutoff. Cox regression model was peformed including the adjustment for the main CAD risk factors. Results Among 3735 included patients, 58.8% had a FIB-4 value above 1.2. Patients with higher FIB-4 score (cutoff= 1.64) were slighly older, presented higher prevalence of male sex, prior PCI and CABG, and prior history of atrial fibrillation and cerebrovascular disease. FIB-4 score was directly associated with higher risk of mortality when addressed as a continouos variable and as a categorical variable (Fig. 1). This relationship was evident in the overall population and in all subsets (PCI, CABG and no revascularization; Fig. 2). Conclusions The use of Fib-4 to determine the degree of liver fibrosis may be powerful to predict mortality in CAD populations which may not show any evident clinical signs of liver dysfunction. The Fib-4 distribution in this trial population, considered as selected and low risk, warrants investigating randomized trial populations having compared on- and off-pump CABG.Figure 1.Mortality: overall population.Figure 2.Mortality: by therapy subsets.

Sex differences in left ventricular dilatation in patients with significant aortic regurgitation: prognostic implications

Abstract Background Left ventricular (LV) dilatation is a strong indicator of adverse outcome in patients with aortic regurgitation (AR). Accordingly, current guidelines recommend the use of LV end-systolic diameter index (LVESDi) as one of the criteria to trigger aortic valve surgery (AVS) in patients with severe AR, but with the same threshold regardless of gender. Purpose To assess sex differences in LV remodeling using both volumetric and linear measurements in a large cohort of patients with significant AR (moderate or greater) and to investigate their prognostic implications. Methods A total of 1070 patients (56 ± 18 years, 691 men) were included. The primary outcome was all-cause mortality. Results Women presented with older age (58 ± 19 vs. 55 ± 17, p=0.023) and more advanced heart failure (HF) symptoms than men (NYHA class III-IV 12% vs. 9%, p=0.017). Men showed significantly larger LVESDi (21 ± 5 vs. 20 ± 5 mm/m2, p=0.013) and LV end-systolic volume index (LVESVi 37 ± 28 vs. 26 ± 17 ml/m2 p<0.001). During a median follow-up of 89 (IQR, 54-132) months, 168 patients died. Women had lower survival rates at 3, 5, and 10 years of follow-up compared to men (92% vs. 94.3%; 85% vs. 89.7% and 75.3% vs. 84.1%, p=0.005) (Figure 1). Spline curve analysis revealed that the threshold of LVESDi associated with an increased risk of mortality was 20 mm/m2 for both sexes. In turn, the threshold for LVESVi was 40 ml/m2 for women and 45 ml/m2 for men. Univariable Cox regression models were constructed separately for men and women. The variables associated with all-cause mortality were age, NYHA class III-IV, and AVS as time-dependent covariate in women, and age, diabetes, AVS as time-dependent covariate, and LAVI (left atrial volume index) in men. These parameters were used as a basal multivariable Cox regression model on top of which LVESDi >20 mm/m2 (Model 1), LVESVi >40 ml/m2 for women and 45 ml/m2 for men (Model 2) were added (Table 1A). LVESVi >40 ml/m2 was not a significant univariate predictor in men. In women, LVESDi >20 mm/m2 (HR: 2.046, 95%CI 1.244-3.419; p=0.006) and LVESVi >40 ml/m2 (HR 1.758, CI 1.095-2.825; p=0.020) showed an independent association with all-cause mortality among other factors (Table 1A). In men, death was independently associated with LVESDi >20 mm/m2 (HR 1.979, 95%CI 1.255-3.121; p=0.003) and LVESVi >45 ml/m2 (HR 2.388, 1.522-3.746; p<0.001), among other factors (Table 1A). Moreover, when added to a basal model that included clinical and echocardiographic variables associated with prognosis, LV dilatation based on volumetric LV enlargement resulted in a greater discriminatory power for both genders (Table 1B). Conclusion Men and women have a similar LVESDi threshold of 20 mm/m2, which is associated with an increased risk of death. However, their respective cut-off values for LVESVi differ, with the optimal threshold for women being 40 ml/m2 and for men 45 ml/m2.

Gut Microbiota and Parkinson’s disease - a prospective analysis of the FINRISK 2002 Study

Abstract Background Parkinson’s disease (PD) is a neurodegenerative movement disorder with mainly unknown etiology. Constipation is a common symptom, and changes in gut microbiota may play role in PD pathogenesis. Previous studies exploring microbial associations to PD have been mostly cross-sectional, and the role of microorganisms in PD etiology remains unclear. Thus, we examined the association between microbiota features and incident PD in a prospective cohort design. Methods In the FINRISK 2002 Study, 7231 participants gave a stool sample that underwent shotgun metagenomic sequencing. Participants with missing stool sample, incomplete covariate data, pregnancy, antibiotic use, and prevalent cases were excluded (final n = 5562). Cox regression models, adjusted for age, sex, education, smoking, coffee consumption, diabetes, cardiovascular events, and constipation, were used to assess associations between incident PD and microbiota features, ie. alpha diversity (the number of different species present in a sample), beta diversity (the differences in microbial composition between individuals), and abundance of 381 core taxa (compositional detection rate of at least 0.1% and a prevalence of 1%). 120 incident cases of PD, identified through register linkage, occurred during a median follow-up of 17.8 years. Results In the multivariate models, PD incidence was not associated with the Shannon index, a measure on alpha diversity, (p-value 0.81), or with the ten first principal component axes in beta diversity analysis (p-values ranging between 0.49-0.91). In permutational analysis, PD did not explain differences in the composition of the gut microbiota (R2 <0.001, p-value 0.46)). None of the core species were associated with PD incidence (all FDR-corrected p-values > 0.05). Conclusions This prospective study showed no support for an association between gut microbiota features and incident PD. Key messages • Previous findings associating gut microbiota with PD may be due to the cross-sectional design, ie. PD affecting the gut microbiota. • Suggestions to screen gut bacteria to identify people at high risk of Parkinson’s disease are vastly premature as the scientific evidence is inconclusive.

Association of osteopontin and shrunken pore syndrome with hospitalization for renal failure in acute heart failure patients

Abstract Background Shrunken pore syndrome (SPS) emerges as a distinctive manifestation of glomerular filtration dysfunction mainly manifested by the impairment of moderate-sized molecular filtration, distinguished by a variance in renal filtration between cystatin C and creatinine. SPS exhibits correlations with adverse prognosis of various cardiovascular diseases. A decline in renal function correlates with a poor prognosis among individuals with heart failure (HF). Osteopontin (OPN), a protein involved to bone mineralization, has been linked to deteriorating renal function and heightened risk for adverse outcomes in patients with chronic kidney disease. Purpose To explore if OPN and SPS are associated with hospitalization for renal failure in patients with acute HF. Methods Cystatin C and creatinine were analyzed in 395 hospitalized HF patients, of which 324 also had osteopontin (OPN) analyzed using a proximity extension assay. SPS was calculated using the CKD-EPI Equations for Glomerular Filtration Rate and defined as a cystatin C-based estimated glomerular filtration rate (eGFR) <60% of the creatinine based eGFR. Hospitalization for renal failure was extracted from regional registries using ICD10 codes N17-N19. Logistic and Cox regression models were deployed to explore a) OPN’s association with SPS; b) OPN’s association with hospitalization for renal failure; and c) SPS’s association with hospitalization for renal failure, adjusting for age, sex, systolic blood pressure and use of renin-angiotensin-aldosterone system (RAAS) inhibitors. Results The study population had a mean age of 74.8 (±12.0) years, 32.4% were women and 104 (26.5%) patients presented with SPS (Table 1). During the median follow-up period of 71 (interquartile range 56-88) months, 35 (8.9%) patients were hospitalized for renal failure. OPN was associated with the prevalence of SPS (OR 1.66; 95%CI 1.08-2.27; p=0.002), as well as with higher risk of hospitalization due to renal failure (HR 2.71; 95%CI 1.61-4.56; p<0.001). Further, also prevalent SPS was associated with higher risk of hospitalization due to renal failure (HR 2.44; 95%CI 1.14-5.24; p=0.022). Conclusions Here, we demonstrate that higher OPN levels are associated with a higher prevalence of SPS and an elevated risk of hospitalization due to renal failure among patients with HF. Additionally, the presence of SPS was associated with a higher risk of renal failure-related hospitalizations. These findings highlight the potential utility of OPN and SPS as biomarkers for identifying heart failure patients at risk of renal function decline, underscoring the importance of early risk stratification and targeted interventions in this population.

Effect of left atrial function on cardiovascular outcome in non-dilated left ventricular cardiomyopathy

Abstract Background This study aimed to determine whether atrial function and strains can provide the greatest or joint incremental prognostic value in patients with non-dilated left ventricular cardiomyopathy (NDLVC) over a long follow-up period. Methods One hundred sixty-four NDLVC patients were included retrospectively. Comprehensive clinical evaluation and echocardiographic investigations were obtained, including measurements of strain derived left atrial (LA) reservoir, conduit, booster strain. All patients were followed up for adverse cardiac events (MACE) including all-cause mortality, hospitalization due to heart failure aggravation. The predictors of MACE were examined with univariable and multivariable Cox regression analysis. Subsequently, nested Cox regression models were built to evaluate the incremental prognostic value of strain parameters. Patient survival was illustrated by Kaplan–Meier curves and differences were evaluated by log-rank test. Results During a median follow-up of 3.8 years, MACEs were identified in 34 (21%) patients. Cox regression models showed that the predictive value of LA conduit strain was independent from and incremental to LAVi and baseline variables. Age, E/e', RASP and LA reservoir and conduit strain were univariably associated with the outcome (all P < 0.05). LA conduit strain was a stronger predictor of outcome compared with reservoir strain. LA conduit strain, age, RASP remained associated in the multivariable model (LA conduit strain HR: 2.14 [95% CI: 1.37-3.87; P < 0.007]; age HR: 1.05 [95% CI: 1.01-1.10; P = 0.020]; and RASP HR: 1.07 [95% CI: 1.01-1.14; P = 0.021]), whereas LVEF, LAVi were not. Adding LA conduit strain to other independent predictors (age and LAVi) improved the prediction of MACEs. (p < 0.05). Also, when a Kaplan Meier graph was obtained for the occurrence of MACE based on LA conduit strain 17%, a significant difference was shown between the two groups. Conclusion LA conduit strain provided the good prognostic value and added incremental value to conventional clinical predictors for patients with NDLVC.Incremental value of LA strainKM according to LA strain 17%

Pregnancy complications and long-term risk of cardiovascular events in women with heart disease

Abstract Background/Introduction Women with congenital heart or acquired heart disease are at increased risk of atherosclerotic cardiovascular disease. Pregnancy complications are established risk factors for cardiovascular disease in the general population, but their prognostic value for cardiovascular outcomes in the population with congenital or acquired heart disease is unknown. Purpose To determine the frequency and prognostic value of pregnancy complications for the risk of cardiovascular outcomes in women with congenital or acquired heart disease. Methods This nationwide registry-based cohort study included women in Sweden with heart disease (pulmonary arterial hypertension, congenital heart disease or acquired valvular heart disease) with singleton births registered in the national Medical Birth Register between 1973 and 2014. Exposures of pregnancy complications (preeclampsia/gestational hypertension, preterm birth or birth of an infant small for gestational age) were collected from the Medical Birth Register, and cardiovascular outcomes (mortality and hospitalizations) from the Cause of Death Register and the National Inpatient Register. Cox regression models were performed with time-dependent covariates, to determine the possible prognostic value of the studied pregnancy complications for cardiovascular outcomes including atherosclerotic cardiovascular disease, heart failure and arrythmias after adjustment for major confounding including smoking and body mass index. Results Among the total of 2,134,239 women included from the Medical Birth Register, 2,554 women with 5,568 singleton births were affected by heart disease. Preeclampsia/gestational hypertension affected 5.8% of pregnancies, preterm birth 9.7%, and birth of an infant small for gestational age 2.8%. Preterm birth (adjusted HR 1.91 (95% CI 1.38-2.64)) was associated with an increased risk of maternal all-cause mortality. Preeclampsia/gestational hypertension (adjusted HR 1.64 (95% CI 1.18-2.29)) and preterm birth (adjusted HR 1.56 (95% CI 1.19-2.04)) were associated with an increased risk of hospitalizations for atherosclerotic cardiovascular disease. Conclusions Pregnancy complications were frequent in women with congenital or acquired heart disease. With a median follow-up time of 22 years, preterm birth was associated with a higher risk of cardiovascular mortality, and preeclampsia/gestational hypertension and preterm birth were associated with cardiovascular morbidity. In women with heart disease, pregnancy complications may provide additional information for the risk assessment of future cardiovascular outcomes.Overview of study designPrevalence and risk estimation

Body mass index and clinical outcomes in patients with diabetes and stable coronary artery disease in THEMIS

Abstract Background Physiologic changes due to extremes of body weight may affect the efficacy and tolerability of antiplatelet treatment. However, it remains unclear whether the risks and benefits of intensified antiplatelet therapy among patients with diabetes and stable coronary artery disease (CAD) are affected by body mass index (BMI). Purpose To assess the relationship between baseline BMI and major adverse cardiovascular (CV) events, and to determine if the effects of ticagrelor vs. placebo varied across the BMI spectrum, in patients with diabetes and stable CAD. Methods THEMIS was a randomized, controlled trial of 19,220 individuals aged ≥50 years with type 2 diabetes and stable CAD, randomly allocated to ticagrelor or placebo on top of aspirin. Patients with a prior myocardial infarction (MI) or stroke, or already on dual antiplatelet therapy, were excluded. The primary efficacy outcome was a composite of CV death, MI, or stroke. The primary safety outcome was TIMI major bleeding. We examined prognostic implications of BMI using 1) restricted cubic splines for the overall trends with outcomes; 2) Cox regression models with predefined BMI intervals (<25 kg/m2, 25-29.9 kg/m2, and ≥30 kg/m2) adjusted for demographic, clinical, and laboratory variables; and 3) Cox regression models for the effects of ticagrelor vs. placebo on outcomes across the spectrum of BMI values (test for interaction). A two-sided P-value <0.01 was considered statistically significant to control the overall chance of type I errors. Results BMI was available in 19,202 (99.9%) participants, with a median of 29 kg/m2 (interquartile range: 26-33). A total of 3352 (17.5%) individuals had a BMI <25 kg/m2, 7644 (39.8%) had a BMI 25-29.9 kg/m2, and 8206 (42.7%) had a BMI ≥30 kg/m2. Median follow-up was 39.9 months (range 0-57), with 1554 primary efficacy events and 306 primary safety events occurring over the course of the study. BMI was not associated with the primary efficacy or safety outcome, or with their individual components. However, BMI was significantly associated with hospitalization for heart failure (HHF) (BMI <25 kg/m2: reference; hazard ratio [HR] for BMI 25-29.9 kg/m2: 1.07, 95% confidence interval [CI], 0.82 to 1.40; HR for BMI ≥30 kg/m2: 1.41, 95% CI, 1.07 to 1.84) and with the composite of HHF or CV death (comparable estimates) after multivariable adjustment (Figure). BMI was also significantly, positively associated with serious adverse events (BMI <25 kg/m2: reference; HR for BMI 25-29.9 kg/m2: 0.99, 95% CI, 0.93 to 1.06; HR for BMI ≥30 kg/m2: 1.20, 95% CI, 1.12 to 1.29). BMI did not modify the risks and benefits of ticagrelor vs. placebo. Conclusions BMI was independently associated with the risk of HHF and the composite of HHF or CV death, but not with other efficacy or safety outcomes, in patients with stable CAD and type 2 diabetes. Ticagrelor was of similar benefit on the primary efficacy outcome vs. placebo across the full range of BMI.

Troponin T as a risk marker for recurrent cardiovascular events in the post-discharge setting one month after acute coronary syndrome: a TRACER substudy

Abstract Background Troponin T (TnT) is a protein found in cardiac myocytes that is released during myocardial injury, such as myocardial infarction (MI). TnT levels rapidly rise during an MI, remain elevated for several days, and are a key criterion for diagnosing MI. Additionally, circulating TnT levels may offer prognostic information later, particularly during the rehabilitation phase after an acute coronary syndrome (ACS). Purpose To examine the relationship between circulating TnT at one month after hospitalisation for ACS and subsequent cardiovascular (CV) events. Methods The TRACER trial randomly assigned 12,944 patients diagnosed with non-ST-segment elevation ACS (NSTE-ACS) to receive either vorapaxar or placebo. Plasma samples were obtained after one month, and high-sensitivity (hs)-TnT was measured among 5,313 patients using the Elecsys electrochemiluminescence immunoassays. In this sub-study, the primary composite endpoint was the one-year risk of CV mortality, MI, or ischaemic stroke. Associations with outcomes were evaluated using Cox regression models, both unadjusted and adjusted for clinical baseline characteristics. Results The median concentration of hs-TnT was 11 ng/L one month after hospitalisation for ACS. Higher levels of hs-TnT at one month were associated with older age, coronary artery bypass surgery during the index ACS, male sex, a history of heart failure, renal disease, and diabetes mellitus. The composite outcome of CV mortality, MI, or ischaemic stroke occurred in 381 patients (incidence rate 5.4 per 100 person-years). Hs-TnT at one month after ACS was independently associated with the risk of the composite CV endpoint (relative hazard ratio with 95% confidence interval comparing the third vs. the first sample quartile: 2.40 [1.80 – 3.20]) (see Figure 2). Similarly, hs-TnT, when added to a model including established risk factors, increased the concordance index of the multivariable model from 0.711 to 0.740 (p<0.001). The results were consistent across the different components of the composite endpoint. Conclusions The level of hs-TnT provides useful information on the risk of future CV events in patients when measured one month after an ACS. This information might be useful for optimising secondary preventive treatment following an ACS.Figure.Hs-TnT and composite CV outcome

Bidirectional relationship between kidney disease progression and cardiovascular events in type 2 diabetes: new Insights from the CANVAS Program and CREDENCE trial

Abstract Background The extent to which chronic kidney disease (CKD) progression increases cardiovascular risk, and whether different types of cardiovascular events affect risk of CKD progression, is incompletely understood. Purpose We sought to explore risk of cardiovascular events before and after CKD progression, and CKD progression before and after different cardiovascular events in patients with type 2 diabetes. Methods We conducted a pooled individual participant data analysis of the CANVAS Program and CREDENCE trial. Using Poisson regression, we assessed the incidence of major adverse cardiovascular events ([MACE] stroke, myocardial infarction, or cardiovascular death) and hospitalised heart failure (HHF) or cardiovascular death before and after CKD progression (defined as 40% decline in estimated glomerular filtration rate [eGFR] or kidney failure), and CKD progression before and after nonfatal cardiovascular events, with no adjustment for confounding related to subgroups defined by post-randomization variables. We estimated the cumulative incidence of all-cause mortality after different nonfatal cardiovascular and kidney outcomes, including different thresholds of CKD progression (kidney failure, 40% or 50% decline in eGFR or doubling of serum creatine) using Cox regression models. Results Among 14,464 participants (mean age 63.7 years, 35.3% female, mean eGFR 55mL/min/1.73m2 and median urinary albumin:creatinine ratio 34mg/g) over a median follow-up of 2.5 years, 1,482, 1,076 and 1,020 experienced MACE, HHF or cardiovascular death, and CKD progression, respectively. After (vs. before) CKD progression, there was an approximate 3-fold increase in incidence of MACE (30.2 vs. 93.8 per 1000-patient-years) and 4-fold increase in HHF or cardiovascular death (21.0 vs. 79.3 per 1000-patient-years). Conversely, the incidence of CKD progression was approximately 1.5-fold higher after (vs. before) nonfatal myocardial infarction or stroke (21.7 vs. 34.1 per 1000-patient-years) and 5-fold higher after HHF (21.2 vs. 108.2 per 1000-patient-years). These patterns were consistent in both treatment arms, with unadjusted incidence rates for clinical events appearing numerically lower in canagliflozin compared to placebo-treated participants (Figure 1). Of all non-fatal cardio-kidney outcomes, HHF and doubling of serum creatine or kidney failure conferred the highest risk of death (Figure 2). Conclusion Atherosclerotic and heart failure risk increases substantially after CKD progression. CKD progression was accelerated after cardiovascular events, particularly HHF. Treatment with canagliflozin was associated with lower event rates before and after a serious cardio-kidney outcome, suggesting continued use of canagliflozin may be beneficial even after cardiovascular events and CKD progression.Figure 1.Figure 2.