Cox Regression Research Articles

Abstract 4133122: Integrative Metabolomic Analysis of Triglyceride-Independent Lipoprotein Lipase Pathway Mechanisms for Coronary Artery Disease

Background: Strong genetic evidence supports the associations between key genes in triglyceride (TG) metabolism via the lipoprotein lipase (LPL) pathway (i.e., LPL , APOC3 , and ANGPTL3 ) and coronary artery disease (CAD). Given sparse human genetic or clinical trial evidence for other TG-modulating pathways, it is unclear if CAD risk reduction is due to reductions in TG levels alone or a secondary mechanism of action. Aim: To determine if there are TG-independent mechanisms of CAD risk reduction specific to the LPL pathway using genomics and metabolomics. Methods: We assessed the genetic effects of LPL pathway genes (67, 46, and 17 SNPs for LPL , APOC3 , and ANGPTL3 , respectively) and non-LPL pathway genes (3462 SNPs) for TG levels and 168 metabolites. We identified metabolites with associated effects that were greater than the associated effects with TG levels for LPL pathway genes and showed heterogeneity compared to the effects for non-LPL pathway genes. Cox proportional-hazards models were used to evaluate the association of candidate metabolites measured at baseline with incident CAD in participants of the UK Biobank. Models were adjusted for age, sex, TG levels, BMI, prevalent type 2 diabetes, statin, and ten PCs of genetic ancestry. Results: Among 233,719 UK Biobank participants free of prevalent CAD and with metabolite measurements, the mean (SD) age was 57.1 (8.0) years, 105,111 (45.0%) were male, and all self-reported as white. Over a median (IQR) follow-up of 11.2 (10.5-11.9) years, there were 7992 (3.4%) incident CAD cases. There were 30, 6, and 93 metabolites with significantly greater genetic effects for LPL , APOC3 , and ANGPTL3 than what was observed with TG levels, respectively. Among 20 metabolites with heterogeneity for ≥2 LPL pathway genes compared to non-LPL pathway genes, multi-variable Cox regression revealed 19 significantly associated with CAD (P<3x10 -4 ). Conclusion: LPL pathway genes have convergent and distinct impacts across metabolites. While LPL and ANGPTL3 have large genetic effects on VLDL metrics, APOC3 may have genetic effects beyond lipoprotein metabolism that impact CAD risk. The extent to which these metabolites influence CAD risk beyond TG alterations requires further study.

Abstract 4135434: Effect of early nutritional guidance for patients with acute myocardial infarction: A single center retrospective cohort study

Introduction/Background: Acute myocardial infarction (AMI) stands as a major global cause of mortality. Various intervention strategies, such as pre-hospital care, reperfusion therapies, pharmacological interventions, dietary modifications, and exercise therapies, have been researched to improve patient prognosis. Research Question: There remains a lack of evidence regarding the impact of early nutritionist-led dietary guidance on the prognosis of AMI patients. Aim: This study aimed to elucidate whether nutritional guidance by nutritionists who have national qualifications would improve the mortality and the primary composite endpoint (including acute decompensated heart failure, stroke, and acute coronary syndrome) of patients following an acute myocardial infarction. Methods/Approach: A retrospective cohort study enrolling 409 AMI patients who underwent emergency percutaneous coronary interventions between September 1, 2015, and October 31, 2023. Nutritionists guided 223 patients (54.5%) during hospitalization in this study. The nutritional guidance used in our study was also based on the definition of adequate caloric intake of 25–30 kcal per ideal body weight (kg). Under an appropriate total energy intake, a fat energy ratio of 20–25% and a carbohydrate energy ratio of 50–60% are recommended, with protein and lipid restrictions depending on the disease state. Results/Data: During a median follow-up of 39 months, 24 cases of all-cause mortality (5.9%) and 6 cases of cardiovascular mortality (1.5%) were recorded. Kaplan–Meier curves demonstrated significantly higher incidence rates of death and primary composite endpoints among patients without nutritional guidance during hospitalization. The multivariate Cox regression model revealed early nutritional guidance as a significant predictor for long-term mortality but not for primary composite endpoints. Furthermore, undernourished patients, defined as those with a geriatric nutritional risk index of 98 or less, showed a similar prognosis to those with good nutritional status after receiving nutritional guidance, indicating that nutritional guidance improves prognosis. Conclusion: Nutritionist-led dietary guidance for patients with AMI can potentially improve total mortality and is expected to be more effective in undernourished patients. Further research is warranted to explore the physiological impacts of improved diets resulting from such guidance and their effects on enhancing prognosis.

Abstract 4126692: Effect of change in different adiposity indices over 10 years on Incident Type 2 Diabetes: The UK Whitehall II Study

Background: It is accepted that obesity increases type 2 diabetes risk. Some studies have explored associations between changes in body mass index (BMI) or waist circumference (WC), 2 indicators commonly used to assess obesity, and diabetes risk separately. However, there are few studies on the effect of change in waist-to-height ratio (WHtR), an index that has been suggested to be more strongly associated with diabetes than BMI and WC, on incident diabetes. Even fewer studies simultaneously examined the associations of change rate in the 3 indices with diabetes. Hypothesis: WHtR change may be more strongly associated with diabetes than BMI and WC. Aims: This study aims to investigate the change rates of BMI, WC, and WHtR in the UK adult population, and compare the effects of different adiposity indices’ changes on diabetes development. Methods: To make facilitate quantitative comparison of BMI, WC and WHtR, we used their standardized values. Repeated measures of the 3 indices were obtained from Phase 3 (1991-94), 5 (1997-99), and 7 (2002-04) of the UK Whitehall II Study (included persons participated in at least 2 of the 3 visits). Mixed effects model was used to calculate individual change rate of the 3 indices. Non-diabetic participants at Phase 7 were then followed up for incident diabetes until Phase 9 (2007-09). We examined the prospective association between change rate of the 3 indicators and diabetes by Cox regression analysis. Results: A total of 5,539 persons were included (mean age at Phase 3 was 49.6 years, 28.8% women). All adiposity indicators increased during Phase 3-7. The overall change rate of WHtR (0.07 SD/year) was higher than BMI (0.04 SD/year) and WC (0.06 SD/year). There were 375 non-diabetic (Phase 7) participants developing diabetes after a median follow-up period of 5.0 years. Initial WC value (HR:1.56) and WHtR value (HR:1.50) showed a stronger association with diabetes than initial BMI (HR:1.27). When the 3 indices increased at the same rate, WC change (HR:3.83, 95% CI: 2.48-5.93) had a higher risk of developing diabetes than changes in WHtR (HR:3.19, 95% CI: 2.19-4.64) and BMI (HR:2.57, 95% CI: 1.85-3.56). Conclusions: The rate of increase over time was higher in WHtR than BMI and WC in this UK adult population. Increases in WC and WHtR were more strongly associated with incident diabetes than BMI. When the 3 indices increased at the same rate, change in WC increased a higher risk of developing diabetes relative to BMI and WHtR.

Abstract 4134692: In-Hospital Mortality Rate and Predictors of 30-Day Readmission in Cancer Patients with MI Undergoing PCI -A Cross Sectional Study From Nationwide Readmission Database

Background and objectives: Data regarding readmission rates and predictors of readmission in cancer patients undergoing PCI are sparce. With the increasing survival rates and prevalence of cardiovascular complications in cancer patients, understanding the patterns and predictors of readmission in this population is paramount for optimizing their outcomes. Cancer patients pose unique clinical challenges due to their combined prothrombotic state and propensity for bleeding. We attempted to identify factors associated with readmission in cancer patients. Methods: We utilized the Nationwide Readmission Database from 2016 to 2020 and included patients more than 18 years of age with primary diagnosis of myocardial infarction(MI) who underwent percutaneous coronary intervention(PCI) and have a preexisting diagnosis of cancer. We used International Classification of Disease, Tenth Revision, Clinical Modification (ICD10 CM) codes to define MI, PCI, and cancer. The primary outcome was the 30-day readmission rate, and secondary outcomes were mortality rates, predictors of readmission, and common causes of readmission. The independent predictors of readmission were analyzed using cox regression analysis. Results: Of the 52,307 cancer patients who underwent PCI, 7,767 were readmitted within a 30-day period. The readmission rate for these patients was 15.70%. The mortality rate was 6.05% for index admission and 6.80% for readmitted cases. Among the readmitted patients in the strongest independent predictor for readmission were leaving against medical advice(AMA), anemia, congestive heart failure, and discharge to a skilled nursing facility or home health. Common causes of readmission within this time included hypertensive heart disease with concomitant CKD stage I-IV and heart failure (6.21%), sepsis (6.12%), NSTEMI (5.60%), hypertensive heart disease with concomitant heart failure (4.62%) and acute kidney injury (1.98%). Conclusions: Thirty-day readmission rate was 15.70%. Independent predictors of readmission were anemia, diabetes mellitus, congestive heart failure, malnutrition, peripheral artery disease, leaving against medical advice, and discharge to facility. Most common cause of readmission was hypertensive heart and kidney disease with heart failure, which comprised 6.21%.

Abstract 4138446: Ceramides Surpass LDL-Cholesterol in Predicting Cardiovascular Mortality in Diabetic and Non-Diabetic Patients

The power of cardiovascular risk prediction is biased by comorbidities (including T2DM), medical treatment, and age, which impact cholesterol levels. Consequently, when applying LDL-C, the true cardiovascular risk of such confounded patients is often underestimated. However, it is not clear whether this constraint for risk prediction may likewise apply to other lipid risk markers in particular ceramides. In this observational cohort study, we recorded cardiovascular mortality for 16 years in 1195 patients. Their median age was 67 years, all of them had a high preexisting cardiovascular risk, 51% were taking statins, and 30% had T2DM. We found a U-shaped association between cardiovascular mortality and LDL-C. We thus stratified the population according to the vertex into high (≥150mg/dL) and lower LDL-C (<150mg/dL) and also according to the T2DM status. A Cox regression analysis revealed that LDL-C failed to predict cardiovascular mortality in any subgroup. In contrast, no U-shaped but a linear association was found for ceramide-based markers. They were able to significantly predict cardiovascular mortality after stratification and even after multivariate adjustment. We thus propose that ceramide-based predictors rather than LDL-C should be applied for a more accurate cardiovascular risk prediction in diabetic and other high-risk patients.

Abstract 4145842: The Incidence, Predictors and Impact of 30-day Readmission of Takotsubo Cardiomyopathy Hospitalization: A Retrospective Nationwide Analysis

Objective: This study aimed to describe the recent readmission and mortality rates of unplanned 30-day all cause readmission after takotsubo cardiomyopathy hospitalization. Methods: We conducted an analysis of the 2020 Nationwide Readmission Database. Using the ICD-10 code, we identified hospitalizations for takotsubo cardiomyopathy. We excluded hospitalizations for age<18years and planned or elective readmissions. To compare baseline characteristics between readmissions and index hospitalizations, Pearson χ2 tests were employed. We utilized multivariate Cox regression analyses to identify independent predictors of readmissions. Results: A total of 7554 patients were hospitalized for index admission for takotsubo cardiomyopathy, and 633 of them were readmitted. The 30-day all-cause readmission rate was 8.5% while specific takotsubo readmission rate was 0.4%. The mortality rate in the index admission was 1.9% and 5.5% in readmitted patients. The mean age of index admission was 67.6years vs 70.7 years in readmission, about 89.0% were female in index admission vs 85.0% in readmission cohorts. The most common reasons for readmission were hypertensive heart disease with heart failure, hypertensive heart disease and chronic kidney disease with heart failure, takotsubo syndrome, sepsis, NSTEMI, COPD exacerbation, acute kidney failure, pneumonia, atrial fibrillation. Readmissions had more acute kidney injury (20.6% vs 11.3%, p-value <0.001) and atrial fibrillation (23.0% vs 13.0%, p <0.001) compared to the index admission, however the index admission had more ventricular tachycardia (4.6% versus 1.8%, p=0.02) compared to readmission cohorts. Readmission had longer length of hospital stay (4.9 days vs 3.7 days, p< 0.001), but less mean total hospital charge of (US$51039 vs US$60617, P =0.008). Older age, acute renal failure, pulmonary disease, coronary dissection, longer length of hospital stays and transfer to rehabilitation facility after discharge were identified as statistically significant predictors of readmissions. Conclusion: About one in twelve patients hospitalized with takotsubo cardiomyopathy were readmitted within 30days. Readmissions had a higher mortality rate; acute renal failure, pulmonary disease, coronary dissection were notable reasons for readmission. Understanding the predictors for readmission highlighted in this study would enable clinicians implement preventive strategies to improve the rate of takotsubo cardiomyopathy readmission

Abstract 4137518: The implications of polygenic versus phenotypic characterization of obesity for cardiovascular-kidney-metabolic health

Introduction: The overall amount and the distribution of body fat, proxied by body-mass index (BMI) and waist-to-hip ratio (WHR), are two important measures of obesity and have significant polygenic heritability. We aimed to investigate whether polygenic scores (PGS) for these traits have additional predictive utility, beyond phenotypic characterization of obesity, for cardiovascular-kidney-metabolic (CKM) health. Methods: We derived PGS for BMI (PGS BMI ) and WHR adjusted for BMI (PGS WHRadjBMI ) using PRS-CS-auto on summary statistics from ~700k individuals of European ancestry (EA) in the GIANT consortium and selecting ~1M common variants for each score. We conducted association analyses in the Atherosclerosis Risk in Communities study, a prospective cohort including 8,631 EA individuals with ascertainment of incident diabetes, hypertension, chronic kidney disease, atrial fibrillation, coronary heart disease, ischemic stroke, and heart failure. We used nested Cox models to measure the added predictive utility of PGS to BMI and WHR for incident CKM phenotypes. Results: The study cohort (age 54.4±5.7 years, 52.4% women, follow-up 24.5±7.6 years) had a baseline BMI of 26.4 kg/m 2 (median [IQR]; 21.6-29.6) and WHR of 0.94 (0.88-0.98). PGS BMI and PGS WHRadjBMI were associated with their phenotypes (partial R 2 ; BMI 0.11 and WHR 0.04, p <0.001), although with a large phenotypic variability across the distribution of PGS (IQR for 1 st and 10 th deciles of PGS; BMI 19.6-28.3 and 22.6-35.9, WHR 0.79-1.03 and 0.87-1.05). Anthropometric measures of obesity were associated with a wider gradient of risk compared to PGS for obesity–most notable for diabetes and cardiovascular phenotypes (Table 1a). Addition of PGS BMI and PGS WHRadjBMI to BMI and WHR resulted in limited improvement in risk discrimination across incident CKM phenotypes (Table 1b). Conclusions: Observed anthropometric measures of obesity are sufficient, and for certain conditions far superior, to capture the risk of incident CKM phenotypes. These findings suggest PGS for adiposity traits likely have limited clinical utility to refine risk stratification for CKM syndrome among middle aged adults.

Abstract 4136289: Aortic Valve Calcium as a Predictor of Chronic Kidney Disease in a Multi-Ethnic Cohort: The MESA Study

Background: Aortic valve calcium (AVC) is associated with an increased risk of cardiovascular disease, non-cardiovascular disease such as dementia, and all-cause mortality. Traditional atherosclerotic cardiovascular disease risk factors are associated with both AVC and chronic kidney disease (CKD), but whether there is an association between AVC and CKD is unknown. Objectives: To ascertain whether AVC quantified by cardiac CT scanning is independently associated with the long-term risk of incident CKD among individuals without a previous history of cardiovascular disease. Methods: We examined 6,346 Multi-Ethnic Study of Atherosclerosis (MESA) participants who underwent cardiac CT scanning at Visit 1 (2000-02) and had an eGFR of ≥ 60 mL/min/1.73 m 2 . AVC was quantified using the Agatston method and categorized as 0, 1-99, and ≥100. Incident CKD was defined as an eGFR < 60 mL/min/1.73 m 2 accompanied with an at least 40% decline in eGFR from baseline, and/or a diagnosis of CKD and indicators of end stage renal disease extracted from hospital records using the International Classification of Disease (ICD) codes. We performed Kaplan-Meier survival curve analyses along with multivariable Cox proportional hazard regression models, adjusted for age, gender, race/ethnicity, highest level of education and traditional cardiovascular risk factors along with coronary artery calcium (CAC), lipoprotein (a) (Lp[a]), and the APOE-ε4 genotype to examine the association between AVC (categorical and log-transformed) and incident CKD. Results: Participants had a mean age 62.2±10.1 years, 53% were women, and AVC >0 was present in 795 (12%) participants. During a median follow-up time of 16.9 years, 982 (15%) participants developed incident CKD. AVC examined as a continuous variable was associated with a significantly increased risk of developing CKD (per log-unit [AVC+1] HR 1.06 [95% CI: 1.02-1.10]; p = 0.005). There was a stepwise increased risk for CKD with higher AVC levels ( Figure ). Similarly, in the multivariable adjusted Cox models, participants with AVC ≥100 had a higher risk of incident CKD, compared with the AVC=0 group (HR 1.48 [95% CI: 1.15-1.89]; p = 0.002). The observed associations remained after further adjusting for CAC score ( p = 0.024), Lp (a) ( p = 0.004), and the APOE-ε4 genotype ( p = 0.004). Conclusions: In a multi-ethnic cohort of participants free of CKD at baseline, AVC was independently associated with a higher risk of incident CKD.

Abstract 4132909: Hemodynamic Indices of Right Ventricular Function Differentially Predict Adverse Clinical Outcomes in Heart Failure with Preserved vs Reduced Ejection Fraction

Background: While the critical role of right ventricular dysfunction (RVD) in heart failure (HF) is increasingly recognized, the prevalence and prognostic impact of RVD across HF subtypes is poorly understood. Research Questions/Aims: We aimed to characterize differences in hemodynamic indices of RV function among patients with HF with preserved vs reduced ejection fraction (HFpEF, EF≥50% vs HFrEF, EF<50%) and to examine associations of RVD with longitudinal clinical outcomes by HF subtype. Methods: We identified patients with prevalent HF undergoing clinically indicated right heart catheterization at Massachusetts General Hospital (2005-2016). We examined three RV hemodynamic indices: right atrial to wedge pressure ratio (RA/PCWP), RV stroke work index (RVSWI), and pulmonary artery pulsatility index (PAPi). We used multivariable linear regression to assess differences in RV indices in HFpEF vs HFrEF. We then used Cox models to examine the association of each index with HF hospitalizations (HFH), major adverse cardiac events (MACE), and death, stratified by HF subtype. Models were adjusted for age, sex, BMI, hypertension, diabetes, lung disease, sleep apnea, and prior MI. Results: Of 2,062 patients (age 66 years, 33% women), 1,242 (60%) had HFrEF and 820 (40%) had HFpEF. RVD (RVSWI <450 mm Hg*ml/m 2 ) was present in 27% of HFrEF vs 21% of HFpEF patients. Those with HFpEF had higher RA/PCWP (β 0.12, SE 0.05, p=0.012) and RVSWI (β 0.22, SE 0.05, p<0.001) relative to HFrEF. Over 4.1 median years follow-up, 915 HFH, 1,066 MACE, and 1,116 death events occurred. Among those with HFrEF, lower PAPi was associated with greater risk of HFH (HR 0.84 (0.77, 0.92); p<0.001) and MACE (HR 0.88 (0.81, 0.96); p=0.003), and higher RVSWI was associated with greater risk of death (HR 1.17, (1.07, 1.27); p<0.001, Figure ). In contrast, in those with HFpEF, only higher RA/PCWP was associated with greater risk of death (HR 1.11 (1.00, 1.23); p=0.042). Conclusion: RVD occurs frequently in both HFrEF and HFpEF, and hemodynamic measures of RV function are associated with greater risk of MACE, death, and HFH. Importantly, the prognostic value of RV indices varied by HF subtype, highlighting key differences in the role of RVD in HFrEF vs HFpEF.

Abstract 4147625: Cardiometabolic Syndrome and Incident Alzheimer’s Disease: The Predicative Value of Age and CMS Using Cox and Machine Learning Models

Background: Cardiometabolic syndrome (CMS) poses a significant public health concern. The study aimed to investigate the predictive value of age and CMS for incident Alzheimer’s disease (AD) in women aged≥50. Methods: A cohort of women aged 50-79 ( n = 63,117) who participated in the Women’s Health Initiative Observational Study (WHIOS) in 1993-1998, without baseline AD and followed through to March 1, 2019, were analyzed. CMS was defined as having ≥3 of five CMS components: large waist circumference, HBP, elevated triglycerides, elevated glucose, and low HDL-cholesterol. AD was classified by physician-diagnoses of incident AD. Hazards ratios (HR) of AD risk associated with CMS by age were analyzed using Cox’s proportional hazards regression analysis. Machine learning (ML)-XGBoost and Lasso Cox models clustered individuals with low, mild, moderate, and severe risk of incident AD. Results: During a median follow-up of 20 years (range: 3.36 to 23.36 years), 8340 developed incident AD. The incident rate (95%CI) of AD was 8.6 (8.1-9.1) per 1000 person-years (PY) in women with CMS, and 7.0 (6.9-7.2) per 1000 PY in those without CMS (p<0.001). Multivariate Cox’s regression analysis indicated that women with CMS versus non-CMS had significantly higher risks of AD in those aged 50-59 [HR (95%CI): 1.37(1.12-1.68)], followed by in those aged 60-69 [1.26 (1.14-1.40)], but nonsignificant in those aged≥70 [1.00 (0.87-1.14)]. Elevated glucose concentration ranked as the top predictor for AD, followed by triglyceride and HBP. Four levels (low to severe) of AD risk were significantly clustered using ML-XGBoost and Lasso Cox models. Conclusions: Women aged 50-69 with CMS vs those without CMS had significantly higher relative risks of AD, but the risk was not significant in those aged≥70. The application of ML prediction models holds potential promise in the early identification of AD risk among U.S. adults.

Changing treatment patterns for hepatocellular carcinoma: A Surveillance, Epidemiology, and End Results-Medicare study.

From 2007 to 2017, sorafenib was the sole systemic therapy for hepatocellular carcinoma (HCC), but nine new therapies were approved from 2017 to 2022. No studies have yet examined population-level treatment patterns for HCC since these approvals. For this retrospective cohort, Surveillance, Epidemiology, and End Results (SEER)-Medicare data were used to identify patients who had HCC diagnosed between 2014 and 2019 with claims through 2020. The authors examined patient characteristics, comorbidities, and receipt of local (e.g., transplantation, resection, embolization) and systemic (e.g., sorafenib, lenvatinib, atezolizumab plus bevacizumab) therapies. Cohort characteristics, treatment patterns, and overall survival (OS) were analyzed, and χ2 tests and t-tests were used to compare treatments between the 2014-2017 and 2018-209 cohorts. Adjusted Cox models were used to compare median OS between treatment groups. Among 11,766 patients (men, 69.2%; White, 76.9%; median age, 71 years), 60.5% received treatment within 1 year, which remained stable over time (2014-2017, 60.4%; 2018-2019, 61.0%; p = .84). The use of local therapy also remained stable (2014-2017, 52.1%; 2018-2019, 52.8%; p = .43), whereas the use of systemic therapy slightly decreased (2014-2017, 17.0%; 2018-2019, 15.2%; p = .01). First-line systemic treatments shifted significantly, with sorafenib use dropping from 84.5% (2014-2017) to 41.3% (2018-2019). The median OS among patients who received no treatment, systemic therapies first, or local therapies first was 2.2, 12.0, and 23.6 months, respectively. Patients who were diagnosed in 2019 had better OS (hazard ratio [HR], 0.80; 95% confidence interval [CI], 0.74-0.86) as did those who received systemic therapy first (HR, 0.33; 95% CI, 0.18-0.61), but survival was worse for those who received local therapy first (HR, 1.41; 95% CI, 1.08-1.84) compared with those who were diagnosed in 2014. Local therapy patterns remained stable, but novel therapies replaced sorafenib as the preferred first-line treatment, improving survival.

Abstract 4123872: Unsupervised clustering analysis of large-scale proteomics data identifies molecular phenogroups of heart failure in a population-based cohort

Background: Heart failure (HF) is a heterogeneous syndrome with high mortality. Previous work characterizing HF subgroups primarily relied on clinical data to cluster patients, an approach constrained by the boundaries of documented clinical features. Clustering based on biomarker data, such as proteomics, may provide insights into underlying molecular processes. However, few studies have used this approach, and all used targeted cardiovascular proteomics panels and a restricted HF ejection fraction group. Hypothesis: We used unsupervised clustering analysis to characterize molecular phenogroups in a population-based HF cohort using a large-scale array of circulating plasma proteins. We hypothesized that distinct proteomic-defined phenogroups would exhibit differences in clinical characteristics, mortality, and protein expression. Methods: We measured 7151 SOMAmers (Slow off-rate modified aptamers) targeting human proteins via the SomaLogic 7K SomaScan assay in 1351 HF patients. After feature selection, 831 SOMAmers were used in k-means clustering of patients via R package “ConsensusClusterPlus.” Phenogroups were compared for clinical characteristics, all-cause mortality, and protein expression. Results: Three phenogroups were identified, exhibiting different clinical characteristics ( Table 1 ) and survival probabilities (5-year survival probability in phenogroup 1: 65% [61%, 68%], phenogroup 2: 45% [40%, 51%], and phenogroup 3: 26% [22%, 30%]). In covariate-adjusted Cox models, membership in phenogroups 2 and 3 was significantly associated with increased rate of mortality compared to phenogroup 1. Phenogroups did not differ by ejection fraction or New York Heart Association class. Pathway overrepresentation analysis of differentially expressed SOMAmers identified pathways associated with inflammatory response and immune cell trafficking. Conclusions: Unsupervised clustering analysis using large-scale proteomics data identified three HF phenogroups with different proteomic signatures, clinical characteristics, and outcomes. Future work is necessary to elucidate how molecular differences contribute to heterogeneity in HF to improve risk stratification beyond current recommended clinical guidelines.

Abstract 4121890: Resting Heart Rate Trajectories over 25 Years: Patterns, Predictors, and Prognostic Impact in the Atherosclerosis Risk in Communities (ARIC) Study

Background: Abnormal resting heart rate (RHR) is associated with cardiovascular events and mortality. Longitudinal RHR trajectories may offer unique prognostic, but research exploring these trajectories over extended periods and their prognostic implications is limited. Methods: Using data from 5,794 participants in the Atherosclerosis Risk in Communities (ARIC) study, we first characterized RHR trajectories over 25 years (from visit 1 [1987-89] to visit 5 [2011-13]) with latent class growth mixture models. Then, we determined the predictors of those trajectories using multinomial logistic regression (n=5,432 with data on predictors of interest). We ran Cox models to quantify the associations between RHR trajectories with cardiovascular outcomes (coronary heart disease, heart failure, stroke) and all-cause mortality (n=4,329 free of cardiovascular disease at baseline). Results: We identified one typical pattern (stable/slight decline, 88.4%) and three atypical patterns (stable-slight increase, 9.2%; increase-decrease, 2.0%; stable-sharp increase, 0.4%) (Figure-Left panel). Obesity, ever smoking, a history of heart failure, and lower education levels predicted the atypical patterns. The stable-increase (combined for slight and sharp) trajectory was significantly and robustly associated with heart failure and all-cause mortality (Figure-Right panel). The increase-decrease trajectory showed a hazard ratio of ~2 for coronary heart disease, although statistical significance was restricted in the demographically adjusted model. Conclusions: We identified one typical (stable/slight decline) and three atypical (increase-decrease, stable-slight increase, and stable-sharp increase) RHR trajectories over 25 years. The atypical trajectories, particularly the stable-increase pattern, were associated with poorer prognosis. These findings highlight the value of monitoring long-term RHR trajectories for cardiovascular risk assessment.

The prognostic importance of glioblastoma size and shape.

Extent of resection, MGMT promoter methylation status, age, functional level, and residual tumor volume are established prognostic factors for overall survival in glioblastoma patients. Preoperative tumor volume has also been investigated, but the results have been inconclusive. We hypothesized that the surface area and the shape were more representative of the tumor's infiltrative capacities, and thus, the purpose of this study was to assess the prognostic value of tumor size and shape in patients with glioblastoma. In total, 271 patients with primary, unifocal glioblastoma were included from two centers in Norway and Sweden, respectively. All tumors were automatically segmented on preoperative MRI scans and manually validated. Tumor volume was used as a measurement of size, whereas sphericity index and area-to-volume ratio defined the shape complexity of the tumor. Contact surface area of the tumor was considered a measurement of both size and shape. Multivariable Cox proportional hazards models were used to assess the prognostic value of the respective tumor measurements, with previously established prognostic factors as covariates. There were no associations between preoperative tumor volume and overall survival. Contact surface area (HR = 1.013, p = 0.002) and sphericity index (HR = 2.223, p = 0.001) were both significant independent prognostic factors for survival in the multivariable Cox models. Contact surface area was also associated with MGMT promoter methylation (p = 0.039) and extent of resection (p = 0.017). Tumor shape complexity appears to be an independent prognostic factor in glioblastoma patients and may also be associated with MGMT promoter methylation status and extent of surgical resection.

Abstract 4138672: Blood Pressure and Cardiovascular Outcomes in Adults with Diabetes and Chronic Kidney Disease

Background: Most international guidelines recommend intensive blood pressure (BP) targets (e.g., <130/80 mm Hg) for patients with chronic kidney disease (CKD). However, the data supporting these recommendations are limited, particularly for those with concomitant diabetes. Hypothesis: Systolic BP (SBP) <130 mm Hg and diastolic BP (DBP) <80 mm Hg are associated with a reduced risk of cardiovascular disease (CVD) in adults with diabetes and CKD. Aims: To determine the association of BP with incident CVD risk among adults with diabetes and CKD. Methods: From a Korean nationwide health screening database, we identified 373,966 adults aged 20-79 with both diabetes and CKD who: (1) underwent baseline health examinations in 2009-2013; (2) had ≥3 BP measurements; and (3) did not have CVD at baseline. The associations of baseline average SBP and DBP with CVD risk were assessed using multivariable-adjusted cause-specific Cox models. The primary outcome was CVD event, defined as a composite of myocardial infarction, stroke, heart failure, or death from CVD. Results: The median (Q1-Q3) age of the participants was 62 (53-70) years; 40.8% were female. Over a median follow-up of 10.2 years, a total of 40,781 incident CVD events occurred. Compared with SBP 130 to <140 mm Hg as the referent group, the multivariable-adjusted HRs (95% CIs) for CVD event in the SBP ≥150 mm Hg, 140 to <150 mm Hg, 120 to <130 mm Hg, and <120 mm Hg groups were 1.34 (1.29-1.39), 1.11 (1.08-1.14), 0.89 (0.87-0.91), and 0.77 (0.74-0.80), respectively. Compared with DBP 80 to <90 mm Hg as the referent group, the HRs (95% CIs) in the DBP ≥100 mm Hg, 90 to <100 mm Hg, 70 to <80 mm Hg, and <70 mm Hg groups were 1.70 (1.56-1.85), 1.19 (1.15-1.24), 0.88 (0.86-0.90), and 0.83 (0.80-0.87), respectively (Figure A). SBP <130 mm Hg and DBP <80 mm Hg were each associated with a reduced CVD risk in a log-linear manner (Figure B, Figure C). The findings were consistent when examining kidney instead of cardiovascular outcomes. Conclusion: Among patients with diabetes and CKD, SBP below 130 mm Hg and DBP below 80 mm Hg were associated with a reduced risk of CVD.

Abstract 4124709: Accelerometer-Measured Sedentary Behavior and Future Cardiovascular Disease

Background: Current consensus guidelines emphasize the importance of achieving 150 minutes or more of moderate to vigorous physical activity (MVPA) per week to promote cardiovascular health but give little guidance about sedentary behavior. Research Question: Is sedentary behavior associated with cardiovascular (CV) disease in a manner distinct from insufficient physical activity? Aims: Examine associations between accelerometer-measured sedentary behavior with risk of specific CV outcomes, including potential interactions with MVPA. Methods: Using 89,530 individuals providing one week of accelerometer-based physical activity data from the UK Biobank, we fit Cox models adjusted for demographic and lifestyle factors to assess associations between sedentary time (as a spline term) and incident atrial fibrillation (AF), myocardial infarction (MI), heart failure (HF), and CV mortality. We assessed the potential effect of MVPA on these associations by including MVPA as an adjustment variable, as well as performing subgroup analyses stratified at the guideline-recommended MVPA threshold. Results: Among 89,530 individuals (age 62±8 years, 56.4% women) undergoing accelerometry, median sedentary time was 9.4 hours/day (quartile-1: 8.2, quartile-3: 10.6). In multivariable models, using the second quartile (8.2-9.4 hours/day) as a referent, sedentary time in the top quartile (>10.6 hours/day) was associated with greater risk of HF (hazard ratio [HR] 1.45, 95% CI 1.28-1.65), and CV mortality (HR 1.62, 95% CI 1.34-1.96), with evidence of a threshold effect at 10.6 hours/day. Higher sedentary time was also associated with greater risk of incident AF (HR 1.11, 95% CI 1.01-1.21) and MI (HR 1.15, 95% CI 1.00-1.32), with an approximately linear relation. Associations with HF and CV mortality persisted after adjustment for MVPA, as well as among individuals both above and below the guideline-based activity threshold of ≥150 minutes MVPA/week. Conclusions and Relevance: Sedentary behavior is broadly associated with future adverse CV outcomes. For HF and CV mortality, associations appear distinct from insufficient MVPA, and sedentary time in excess of 10.6 hours/day conferred an increased risk.

Abstract 4123849: Respiratory Syncytial Virus (RSV) Cases Involving Hospitalization Are Associated with an Increased Risk of Myocardial Infarction and All−Cause Mortality Among Adults Aged 50 Years and Older

Background: Older adults and adults with comorbidities are at increased risk for severe respiratory syncytial virus (RSV) disease and related complications. Aims: To estimate the risk of myocardial infarction (MI) and all−cause mortality among adults aged ≥50 years hospitalized with RSV compared to those with no recent acute respiratory illness (ARI) and those hospitalized with influenza. Methods: Data from Optum’s de−identified Clinformatics® Data Mart Database were analyzed (October 2015–June 2023) in this retrospective cohort study. Adults aged ≥50 years with ≥12 months of continuous enrollment were assigned to cohorts based on RSV or influenza hospitalization (from ICD−10 codes; RSV and flu cohorts) or no recent ARI (control cohort). Index dates for RSV and flu cohorts were the start of an ARI that included hospitalization. Baseline characteristics were measured in the 12 months pre−index. MI (from ICD−10 codes) and all−cause mortality were measured during follow−up and compared between cohorts using time−varying coefficient multivariable adjusted Cox models (MI results accounted for the competing risk of death). Results: In the RSV cohort (n=14,759), mean age (76.5 years) and mean Charlson comorbidity index (CCI; 3.3) were higher than the flu (n=77,468; 75.4 years, CCI=2.9) and control (n=73,795; 69.5 years, CCI=1.0) cohorts. Adjusted HRs (95% CI) for MI and all−cause mortality risk were significantly higher in the RSV vs control cohort across follow−up, ranging from 30.96 (26.22–36.54) within 30 days post−index to 2.26 (2.04–2.51) >365 days post−index for MI and 10.77 (9.19–12.63) within 30 days post−index to 2.29 (2.18–2.42) >365 days post−index for mortality. Compared to the flu cohort, adjusted MI and mortality risk in the RSV cohort were lower during the 30 days post−index (MI: 0.87 [0.82–0.92]; mortality: 0.84 [0.78–0.90]) but higher >365 days post−index (MI: 1.11 [1.01–1.22]; mortality: 1.05 [1.01–1.10]). Conclusion: MI and all−cause mortality risk were higher for hospitalized RSV cases compared to controls. Smaller differences in outcomes were observed when comparing hospitalized RSV cases with hospitalized influenza cases, with varying direction over time. With existing evidence of increased MI and mortality risk after influenza and these findings on MI and mortality risk after RSV, future research should aim to further understand the impact of RSV on cardiovascular outcomes and assess the role of RSV prevention in lowering the risk of MI and mortality.

Abstract 4124226: Long-term exposure to air pollutants and incidence of cardiovascular disease events and mortality in The Multi-Ethnic Study of Atherosclerosis and Air Pollution (MESA Air)

Introduction: Exposure to ambient air pollution may increase the risk of cardiovascular disease events and mortality, but prior publications have primarily included administrative cohorts with outcomes that have not been individually reviewed and with air pollution estimates created without cohort-specific exposure monitoring. Multi-Ethnic Study of Atherosclerosis (MESA) is a multi-site cohort study designed specifically to prospectively collect and adjudicate cardiovascular disease (CVD) events. MESA Air recruited additional participants into sub-cohorts for enhanced air pollution variation and sample size. Research Question: The aim of this analysis was to characterize the relationship between long-term exposure to nitrogen dioxide (NO 2 ) and fine particulate matter (PM 2.5 ) and all-cause mortality and CVD events. Methods: Air pollution exposure was assessed using address history with a purpose-built exposure model incorporating cohort-specific monitoring including measurement and validation at participant homes. We used Cox models to assess the risk of rolling 2-year average exposures on all cause-mortality and on a composite CVD endpoint (definite angina, probable angina with revascularization, myocardial infarction, atherosclerosis or other CVD death, resuscitated cardiac arrest, and stroke). Models were stratified for baseline hazard by age, sub-cohort, and recruitment year and were additionally adjusted for age, sex, race/ethnicity, field center, smoking/second-hand smoke, pack-years, physical activity, education, income, neighborhood socioeconomic status, and statin use. Results: MESA Air participants were aged 44-87 years at enrollment between 2000 and 2007; follow-up averaged 14 years. 6,915 participants had follow-up for events, NO 2 exposure, and covariate information. We observed 1,442 deaths and 985 CVD events. The interquartile range over all 2-year averages was 10.5-23.1 ppb for NO 2 and 10.1-14.9 µ/m 3 for PM 2.5 . The adjusted hazard ratio (aHR) for a 10 ppb increment in NO 2 was 1.38 (95% CI: 1.17, 1.64) for all-cause mortality and 1.16 (95% CI: 0.95, 1.42) for incident CVD events. The aHR for a 5 µg/m 3 increment in PM 2.5 was 1.20 (95% CI: 0.99, 1.46) for all-cause mortality and 1.15 (95% CI: 0.95, 1.39) for incident CVD events Conclusions: These results add to growing literature demonstrating an association between air pollution exposure, mortality, and CVD in a cohort with well-characterized clinical endpoints and cohort-specific exposure assessment.

Abstract 4136285: Large-Scale Proteomics Identifies Novel Shared Biomarkers of Heart Failure and Cancer: the Atherosclerosis Risk in Communities (ARIC) Study

Introduction: There is a bidirectional relationship between cancer and cardiovascular disease risk. Identifying proteins associated with both cancer and heart failure (HF) may provide insight into common biological pathways underlying both conditions. Methods: Among 10,136 participants in the community-based ARIC cohort study who were free of HF and cancer at study visit 2 (1990-92) and had aptamer-based proteomics (SomaScan v4), we assessed the association of 4,955 plasma proteins with incident HF and with incident site-specific cancer ascertained by cancer registry linkage supplemented with medical records (lung, post-menopausal breast, prostate, colorectal, and hematologic) using multivariable Cox models adjusted for demographics, clinical characteristics, and social determinants of health. Two-sample cis-Mendelian randomization ( cis- MR) was performed to evaluate potential causal effects of proteins on HF, left ventricular (LV) function, and site-specific cancer. Results: Mean age at baseline was 56±6; 54% were female; and 24% reported black race. Over a median follow-up of 10 [IQR 10, 10] years, there were 604 incident HF events and 1,207 incident cancers (169 lung, 85 hematologic, 105 colorectal, 206 breast, 288 prostate). Using a Bonferroni significance threshold (p < 1.0x10 -5 ), 23 proteins were associated with both HF and lung cancer, 2 with HF and hematologic malignancy, 1 with HF and colorectal cancer, and none with HF and breast or prostate cancer. Six proteins remained significantly associated with both HF and lung cancer after further adjustment for pack-years of smoking (Figure). In cis- MR of these six proteins, ICAM5 and MMP12 showed potential causal effect on LV volume and lung adenocarcinoma, and PLAUR showed potential causal effect on HF and lung adenocarcinoma. Conclusion: Among various types of cancer, proteins associated with lung cancer showed the greatest overlap with proteins associated with HF, which was largely accounted for by smoking exposure. We uncovered a set of 6 plasma proteins associated with both incident HF and lung cancer after accounting for smoking. MR identified proteins with potential causal effects on both lung adenocarcinoma and LV size (ICAM5, MMP12) and HF (PLAUR).

Abstract 4144573: Cardiac biomarkers, intensive lifestyle intervention, and risk of heart failure subtypes in type 2 diabetes – a post-hoc analysis of the Look AHEAD trial

Background: N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (hs-cTnT) identify subclinical heart failure (HF) in type 2 diabetes (T2D). The contribution of changes in cardiac biomarkers to HF risk, particularly HF subtypes, is unclear. Whether HF risk associated with cardiac biomarkers is modifiable with an intensive lifestyle intervention (ILI) targeting weight loss is unknown. Methods: Adults with T2D and overweight/obesity in the Look Action for Health in Diabetes (AHEAD) trial without prevalent HF were included. NT-proBNP and hs-cTnT were measured at baseline, 1- and 4-years (Roche Diagnostics). Adjusted Cox models were created to evaluate the associations of baseline, 1- and 4-year change in NT-proBNP and hs-cTnT with risk of HF with preserved and reduced ejection fraction (HFpEF and HFrEF, respectively). Interaction testing was performed to evaluate heterogeneous effects of the ILI vs diabetes support and education (DSE) across baseline cardiac biomarkers. Results: Of the 3,959 participants included, 212 had incident HF (108 HFpEF, 84 HFrEF) over 12 years. Higher baseline NT-proBNP and hs-cTnT were each significantly associated with higher risk of HFpEF and HFrEF ( Table) . Increases in NT-proBNP over 1- and 4-years were significantly associated with higher risk of HFpEF and HFrEF with a similar pattern of association for hs-cTnT and HF subtypes. After accounting for risk factor changes, the association of 1- and 4-year changes in NT-proBNP, but not hs-cTnT, with risk of HF subtypes remained significant. There was a significant interaction between NT-proBNP and ILI for risk of HFpEF but not HFrEF (p-int = 0.001). The ILI reduced HFpEF risk among participants with elevated (≥125 pg/mL) but not non-elevated NT-proBNP (<125 pg/mL) (ILI vs DSE HR [95% CI]: 0.48 [0.25-0.93] and 1.67 [0.94-2.94], respectively). No significant treatment group by hs-cTnT interactions were identified. Conclusions: In T2D, longitudinal changes in cardiac biomarkers, particularly NT-proBNP, are significantly associated with HF risk, independent of risk factor changes. In Look AHEAD, elevated NT-proBNP may identify individuals who are more likely to benefit from the ILI for HFpEF prevention.