Systolic Blood Pressure Research Articles

Abstract 4116177: Metabolic and Pharmacokinetic Profiling of Ketone Ester by Background SGLT2 Inhibitor Therapy in Heart Failure with Reduced Ejection: A Phase I Clinical Trial

Background: Growing evidence supports a therapeutic role for ketones in HFrEF. However, no pharmacokinetic (PK) studies are available to guide further investigation, and uncertainty exists regarding use with the ketogenic SGLT2i and dose-dependent effects. Methods: We conducted a phase I trial of two doses of ketone ester (KE, 250 mg/kg and 500 mg/kg) in 20 HFrEF participants, stratified by SGLT2i use. Non-compartmental analysis assessed PK parameters of ketones. Paired t-tests and generalized linear mixed models assessed changes in mass-spectrometry based targeted metabolites, blood gas, and vital sign assessments up to 4 hours after dosing. Results: The mean age was 66.0±14.8 years, 45% were women, 30% were non-White, and average EF was 33±13%. The median (25 th –75 th percentile) T max , C max , and T 1/2 for total ketones with 250 and 500 mg/kg doses were 1.01 (0.64-1.24) and 1.58 (1.06-1.99) hours, 2317 (2165-2491) and 3354 (3291-3538) µM, and 0.85 (0.66-1.24) and 2.04 (1.36-3.47) hours, respectively ( Figure 1A ). One hour after KE consumption, insulin levels robustly increased, while non-esterified fatty acids, branched-chain amino acids, and acylcarnitines decreased except for C2/C4-OH acylcarnitines, which increased (FDR-adjusted p-value<0.05). Increases in ketones and C2/C4-OH acylcarnitines were dose-dependent, while background SGLT2i was associated with blunting of the decrease across acylcarnitines. One hour post KE, heart rate initially rose by 4 (95%CI 2-6) beats/min, while systolic blood pressure (-7, 95%CI -12, -2 mmHg), pH (-0.07, 95%CI -0.08, 0.05), and bicarbonate (-3, 95%CI -4, -2 mEq/L) decreased, with dose-dependent acid-based effects ( Figures 1B-C ). These values returned close to baseline by 4 hours. Adverse events were infrequent and mild. Conclusions: Acute KE ingestion is associated with rapid changes in several key metabolic pathways, with differential effects imparted by background SGLT2i (fatty acid metabolism) and dose (ketone metabolism). Hemodynamic effects were transient and irrespective of dose/SGLT2i, while acidotic effects were heightened with increasing dose. These data support the safety of combined KE and SGLT2i in HFrEF and provide grounding data for further trials.

Abstract 4125587: Vasomotor function and its regulation by perivascular adipose tissue in metabolic syndrome vary depending on severity and combination of metabolic parameters

Metabolic syndrome (MetS) is a cluster of risk factors for cardiovascular disease. Because perivascular adipose tissue (PVAT) regulates arterial tone by releasing vasorelaxing/vasocontracting factors, the effects of PVAT on vasomotor function have been heterogeneously reported. Various PVAT functions can result from the severity or combination of metabolic parameters in MetS. Therefore, we compared the effects of mesenteric arterial PVAT on the nitric oxide-dependent vasorelaxation response among the three metabolic syndrome (MetS) model strains. We compared male OLETF, Zucker fatty (ZF), and SHRSPZF (SPZF) rats aged 20 weeks to lean controls, LETO, ZF +/+ , and Wistar-Kyoto (WKY) rats. To determine the effects of PVAT on vasodilators, we used organ bath techniques to assay nitroprusside-induced relaxation of isolated mesenteric arterial ring preparations with intact or removed PVAT. The waist circumference to length ratio in OLETF and ZF rats was higher than that in SPZF rats, and the systolic blood pressure was higher in SPZF rats than in the other groups. In the serum, there was no significant difference in triglyceride levels. Still, glucose and thiobarbituric acid reactive substance levels were higher in OLETF and SPZF rats than in ZF rats. Relaxation in ZF rats did not change compared to that in ZF +/+ rats and the presence of PVAT. In contrast, relaxation in OLETF rats was lower than in LETO rats, and there was no difference between the presence and absence of PVAT. However, relaxation in SPZF rats was lower than in WKY rats, and relaxation increased to the same level as in WKY rats in the presence of PVAT. This study unveils novel insights, suggesting that high serum glucose and oxidative stress cause arterial dysfunction, whereas high blood pressure induces PVAT functional changes. These findings underscore the complex interplay between metabolic disorders and vascular health, potentially paving the way for more targeted interventions in patients with MetS.

Abstract 4131796: Non-Contact Biometric System for Early Detection of Hypertension and Diabetes Using AI and RGB Imaging

Introduction: In recent years, the development of wearable devices and bioinformation analysis applications utilizing smartphone sensors has seen significant advancements. Despite these technological strides, their adoption and sustained use remain limited to health-conscious individuals. The general populace, particularly those indifferent to health management, stands to miss out on the potential benefits of wearable technologies due to a lack of engagement. This disconnect underscores the necessity for more accessible health monitoring solutions. Research Questions and Goals: This study aims to bridge the gap in health monitoring accessibility by introducing a system capable of non-invasive, non-contact acquisition of biometric information. Such a system seeks to democratize the early detection and prevention of diseases across various demographics. Methods and Results: A prospective cohort clinical study was conducted in a hospital setting with approximately 200 consenting patients and healthy controls. Images of the subjects' faces and hands were captured with a high-speed camera, and blood pressure measurements were taken simultaneously for correlation. A machine learning algorithm was developed to analyze skin blood flow and spectral features from these images to identify potential diseases. The study specifically focused on early detection of hypertension and diabetes. Hypertension was categorized for individuals with systolic blood pressure ≥115 mmHg or diastolic blood pressure ≥75 mmHg. Diabetes was identified in subjects with HbA1c levels ≥6.5 or those previously diagnosed. The algorithm's performance in detecting hypertension showed a 94.2% in alignment with the AHA guidelines for stage1 hypertension, based on pulse wave features. For a subset including 40% early hypertension cases, accuracy rates were 86.2% for 30-second data segments and 80.9% for 5-second segments. For diabetes detection, the application of the algorithm to video data achieved a 75.3%, utilizing blood flow patterns as markers. Hypertension and diabetes were analyzed using different features. Conclusions: The integration of AI algorithms with video data analysis of skin and blood vessels demonstrates a promising avenue for the non-contact, early detection of hypertension and diabetes. This approach not only offers a viable non-contact monitoring technology, but also represents a significant leap towards inclusive, accessible health care prevention and management strategies.

Do sociodemographic and health predictors affect the non-insulin-based insulin resistance index? A cross-sectional study.

Insulin resistance (IR) is considered a risk factor for cardiovascular diseases (CVD). Therefore, early diagnosis of IR is clinically significant for primary and secondary CVD prevention initiatives. In addition, non-insulin metabolic indices may be useful for diagnosing IR. The first objective was to estimate the triglyceride and glucose (TyG) index and the metabolic score for insulin resistance (METS-IR) index values in a local community with high social deprivation and increased cardiovascular risk according to the Systematic Coronary Risk Evaluation scale. The second objective was to identify significant sociodemographic and health predictors for the TyG index and METS-IR index. This cross-sectional study was conducted in the local community of Janów district in eastern Poland and consisted of 2 stages. The 1st stage involved basic research (n = 4,040), while the 2nd stage involved enhanced diagnostics (n = 2,657). Data from the 2nd stage was used for the analyses. Anthropometric and physiological measurements were taken, blood was drawn for laboratory tests, selected sociodemographic and health variables were evaluated, and the TyG index and METS-IR index were calculated. The mean TyG index score in the study group was 8.65 (±0.58), and the mean METS-IR index score was 41.45 (±9.02). Both indices were significantly associated with age, male sex, smoking, and systolic blood pressure (SBP) in a multivariable model. In addition, alcohol consumption and body mass index (BMI) were significantly correlated with the TyG index, whereas education was significantly associated with the METS-IR index. Our results show the association between IR and sociodemographic and health variables in a group with a high social deprivation rate and increased cardiovascular risk. Early detection of cardiometabolic risk is important for both primary and secondary CVD prevention. In primary healthcare, this can be accomplished through surrogate markers of IR.

Abstract 4138292: Smoking cessation is linked to regression of electrocardiographic left ventricular hypertrophy

Introduction/Background: Electrocardiographic left ventricular hypertrophy is a strong predictor of cardiovascular morbidity and mortality. Further, smoking cessation provides a range of health benefits; however, its association with left ventricular hypertrophy is unclear. Research Questions/Hypothesis: What impact does smoking cessation have on left ventricular hypertrophy regression? Goals/Aims: We investigated the association between smoking cessation and regression of left ventricular hypertrophy. Methods/Approach: We compared electrocardiographic left ventricular hypertrophy between baseline and 6 years after smoking cessation follow-up visits in 752 non-hypertensive subjects (695 males, 47.8±9.2 years), from available datasets of 234 596 health check-ups. Left ventricular hypertrophy on ECG was assessed using the Sokolow-Lyon voltage criteria: SV1+RV5 (mV), with left ventricular hypertrophy defined as >3.5 mV. Results/Data: After 6 years of smoking cessation, body weight was found to increase (from 65.7±10.5 to 68.1±10.8 kg, p <0.0001) and systolic blood pressure also increased (from 112.9±12.7 to 122.0±14.2 mmHg, p <0.0001). Nevertheless, left ventricular hypertrophy on ECG regressed significantly (from 2.47 to 2.41 mV, p <0.0001), and the proportion fulfilling the criteria for left ventricular hypertrophy also decreased from 8.4 to 6.5%. In addition, the antihypertensive drug prescription rate due to elevated blood pressure after 6 years was 13.7% (103/752). Therefore, the regression of left ventricular hypertrophy with or without antihypertensive drug use was assessed. The results showed that left ventricular hypertrophy regressed significantly both [2.68→2.45 mV ( p <0.0001)] and [2.44→2.40 mV ( p =0.01)] in the groups administered (n=103) and not administered (n=649) antihypertensive drugs, respectively. Conclusions: Smoking cessation was found to be associated with regression of electrocardiographic left ventricular hypertrophy, despite being potentially associated with future weight gain, increased blood pressure, and with or without antihypertensive drugs. The results indicated that the health benefits of left ventricular hypertrophy regression from smoking cessation may outweigh the negative effects of weight gain and increased blood pressure from smoking cessation.

Abstract 4137735: Chronic Oxidative Stress Induces Hypertension and Abdominal Aortic Aneurysm in Chemogenetic Mice Model

Background: Aortic aneurysms account for ~10,000 deaths annually in the USA. Oxidative stress is implicated in both abdominal (AAA) and thoracic (TAA) aneurysm formation, but the mechanisms are incompletely understood. We used a chemogenetic approach to modulate oxidative stress in the vascular wall by creating a transgenic mouse (DAAO-TG Tie2 ) that expresses yeast D-amino acid oxidase (DAAO) driven by the endothelial Tie2 promoter. DAAO generates the reactive oxygen species hydrogen peroxide from D-amino acids. Vascular tissues contain L-amino acids, so yeast DAAO is quiescent until DAAO-TG Tie2 mice are provided with D-amino acids. Here we characterize the cellular and molecular consequences of vascular oxidative stress in DAAO-TG Tie2 mice. Hypothesis: Chronic oxidative stress in the vascular wall causes arterial dysfunction. Aim: To characterize the phenotype of DAAO-TG Tie2 mice after oxidative stress induction in vascular endothelium. To identify the mechanisms whereby vascular oxidative stress causes arterial dysfunction and hypertension. Methods: Systolic blood pressure and aortic sonography were measured weekly in D-alanine-fed DAAO-TG Tie2 . Proteomic analyses were used to identify mechanistic targets, which were validated using biochemical and immunohistochemical methods. Results: D-alanine-fed DAAO-TG Tie2 mice develop systolic hypertension and abdominal but not thoracic aortic aneurysms; treated mice die in >3 months with burst abdominal aortic aneurysms. Transgene expression is similar in abdominal and thoracic endothelium. Levels of oxidative stress markers (oxidized proteins, lipid, and DNA) were similar in thoracic and abdominal aorta. Proteomic analyses established phenotypic switching in abdominal but not thoracic aorta, and also revealed activation of the oxidant-activated kinase ASK1 and of the MAP kinase cascade in abdominal but not thoracic aorta. Immunoblot analyses showed a marked decrease in JNK1 phosphorylation by phosphatase DUSP3 and an increase in vascular KLF4, leading to phenotypic switching of contractile to synthetic VSMCs. Conclusion: Chronic chemogenetic oxidative stress induces hypertension and abdominal aortic aneurysm formation caused by KLF4-dependent VSMC phenotypic switching.

Factors and machine learning models for predicting successful discontinuation of continuous renal replacement therapy in critically ill patients with acute kidney injury: a retrospective cohort study based on MIMIC-IV database.

For critically ill patients with acute kidney injury (AKI), there remains controversy regarding the predictive factors affecting the discontinuation of continuous renal replacement therapy (CRRT). This study aims to explore factors associated with successful CRRT discontinuation in AKI patients and to develop predictive models for successful discontinuation. We conducted a retrospective study on adult patients with AKI who received CRRT, sourced from the Medical Information Mart for Intensive Care (MIMIC-IV) database. Successful discontinuation of CRRT was defined as no CRRT requirement within 72h after stopping CRRT. Predictive factors for successful discontinuation of CRRT were analyzed. Additionally, we utilized machine learning algorithms to develop predictive models, including logistic regression (LR), decision tree (DT), random forest (RF), XGBoost, and K-nearest neighbor (KNN). A total of 599 patients were included, of whom 475 (79.3%) successfully discontinued CRRT. Urine output, non-renal SOFA score, bicarbonate, systolic blood pressure, and blood urea nitrogen were identified as risk factors for successful CRRT discontinuation. The KNN model exhibited the highest area under the receiver operating characteristic curve (AUC) (0.870), followed by LR (0.739), DT (0.691), RF (0.847), and XGBoost (0.830). When incorporating all available variables, the AUCs for the LR, DT, RF, XGBoost, and KNN models were 0.708, 0.674, 0.875, 0.866, and 0.816, respectively. Considering the performance of the models in both scenarios, the ensemble learning models (RF and XGBoost) were demonstrated superior performance. Our results identified factors associated with successful discontinuation of CRRT in AKI patients. Additionally, we developed promising machine learning models which provided a reference for future research.

Prevalence of Hypertension and Prehypertension among Young Adult Students of Midnapore Town, Paschim Medinipur, West Bengal, India

Background: Hypertension is one of the most prevalent public health concerns and also one of the prominent factors in affecting the cardiovascular diseases (CVDs), coronary heart diseases (CHDs). It has been termed as “Silent Killer’. About 46.0% of adults worldwide with hypertension are unaware that they have the condition. Methods: The present study aimed at the investigation on the anthropometric, derived variables and blood pressure variables. It also determined the correlation between anthropometric, derived variables and blood pressure variables. It estimated the prevalence rate of hypertension and prehypertension among the young adult students of Midnapore Town, Paschim Medinipur, West Bengal, India. The cross-sectional study was conducted among 201 young adult male students aged between 18 to 28 years. Height (HT), Weight (WT), Mid upper arm circumference (MUAC), Hip circumference (HC), Waist circumference (WC), Biceps skinfold (BSF), Triceps skinfold (TSF), Subscapular skinfold (SSF) and Suprailliac skinfold (SISF), Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) and pulse rate measurement were taken using standard procedure. Results: The overall prevalence of hypertension was found to be 10.9% among the studied participants and 44.3% was the prehypertension prevalence rate. A significant correlation (p<0.05) was found between blood pressure variables and different anthropometric and derived variables. Conclusion: This study demonstrated that there is a very strong prevalence of prehypertension and HTN among the young adult students of Midnapore town. Results of such kind of researches can be helpful in the formulation of appropriate awareness programmes in the universities and colleges.

Abstract 4120670: Pericoronary Adipose Tissue Inflammation as a Marker of Increased Coronary Plaque Burden in Patients With Chronic Coronary Artery Disease With Zero Calcium Score

Background: Dysfunctional or excess adiposity plays pivotal role in the development of coronary atherosclerosis. It remains unclear whether pericoroanry adipose tissue (PCAT) inflammation is associated with increased coronary plaque burden in its early stage of atherosclerosis, independent of traditional coronary risks or cardiovascular-kidney metabolic health. Purpose: To investigate the association of PCAT inflammation with coronary plaque burden in patients with newly suspected with chronic coronary artery disease (CAD) and zero calcium score who underwent coronary computed tomography angiography (CCTA). Methods: This retrospective CCTA study consists of 294 chronic CAD patients with zero calcium score (59 years, male 51 %). Chronic CAD was defined as stable condition with presence of increased non-calcified plaque burden on CCTA (Figure 1A-D). PCAT attenuation (PCATA) was assessed by fat attenuation index in the major three coronary arteries (right coronary artery, RCA; left anterior descending artery; LAD, and left circumflex coronary artery, LCX)(Figure 1C and D). Multivariable analysis using linear regression model was performed to determine independent predictors of increased %PV by adjusting for traditional coronary risks, metabolic risks, and chronic kidney disease (CKD). Hisayama Risk Score (HRS) was calculated to estimate 10-year cardiovascular risks. Results: Mean %plaque volume (PV) and PCATA-RCA was 44±4.0％ and -77±8.8 HU. %PV was correlated with age (p<0.05), systolic blood pressure (p<0.05), non-HDL cholesterol (p<0.05), Hisayama risk score (p<0.05, Figure 2), PCATA-RCA (p<0.001, Figure 3), PCATA-LAD (p<0.001), and LCX-PCATA (p<0.001). In a multivariable linear regression model adjusting for age, sex, hypertension, diabetes, dyslipidemia, and current smoking (model 1), PCATA-RCA was independently associated with %PV [beta, 0.17; 95% confidential interval (CI) 0.115-0.217, p < 0.001]. In a model adjusting for age, sex, metabolic syndrome, body mass index ≥23kg/mm 2 , and CKD (model 2), PCATA-RCA (beta, 0.18; 95% CI 0.128-0.232, p<0.001) and high-risk HRS (beta, 3.1; 95% CI 1.35−4.87, p<0.001) were independently associated with %PV. Similarly, independent associations of PCATA in LAD and LCX with %PV was observed. Conclusion: This study demonstrates that PCATA is a robust marker related to increased burden of coronary atherosclerosis even in the early stage of atherosclerosis as defined by zero coronary artery calcium score.

Abstract 4127990: Inactive Matrix Gla Protein and Cardiovascular Outcomes: the Multi-Ethnic Study of Atherosclerosis

Background: Matrix Gla protein (MGP) inhibits arterial calcification. Higher inactive MGP, dephosphorylated-uncarboxylated (dp-ucMGP), is positively associated with vascular calcification, possibly portending cardiovascular events. The objective was to determine the association of dp-ucMGP with incident cardiovascular disease (CVD) events and mortality in the Multi-Ethnic Study of Atherosclerosis (MESA). Methods: MESA is a cohort study of 45-84 year-old individuals enrolled between 2000-02 with adjudicated outcomes through 2019. Dp-ucMGP was measured at baseline in n=2663 participants with cardiac computed tomography at Exams 1 (2000-02) and 5 (2010-12). Using age-stratified Cox proportional hazard models, adjusted for sex, race-ethnicity, body mass index, systolic blood pressure, statin use, anti-hypertensive medication use, smoking status, physical activity, alcohol use, diabetes, high density lipoprotein, low density lipoprotein, triglycerides, phosphate, and estimated glomerular filtration rate, we determined the association of dp-ucMGP with risk of all CVD (mean follow-up 16 + 4 years), hard CVD (17 + 3 years), hard CHD (17 + 3 years), and all-cause mortality (18 + 2 years). Results: The youngest age quartile (45-53-years-old) with higher dp-ucMGP levels (520-2934 pmol/L) had an increased risk of all CVD (HR 3.01 [95% CI 1.56, 5.80], p=0.001), hard CVD (HR 2.78 [95% CI 1.29, 6.02], p=0.009), hard CHD (HR 3.37 [95% CI 1.29, 8.81], p=0.013) and all-cause mortality (HR 2.69 [95% CI 1.06, 6.79], p=0.037) compared to dp-ucMGP levels between 150-519 pmol/L in maximally adjusted models. There was no relationship with any outcomes for the other age quartiles (Table). Conclusions: Middle aged individuals with elevated dp-ucMGP levels ( > 520 pmol/L) had an increased risk of incident CVD, CHD, and all-cause mortality.

Abstract 4112845: Trends in Cardiovascular Risk Factors Among Children and Adolescents by Race and Ethnicity and Socioeconomic Status, 1999-2020

Background: Recent findings from large-scale cohort studies indicate that risk factors such as body mass index (BMI), systolic blood pressure (SBP), total cholesterol (TC), triglyceride (TG), and smoking during youth, starting in early childhood and adolescence, are associated with cardiovascular events and cardiovascular-related mortality in adulthood. The secular trends of cardiovascular risk factors among US children and adolescents remain unclear. Objectives: To examine 20-year trends in cardiovascular risk factors in the children and adolescents population by race and ethnicity and by socioeconomic status. Methods: The primary objective of the NHANES is to evaluate the overall health and nutritional status of the U.S. population. In this analysis, data from ten NHANES survey cycles, conducted from 1999-2000 through 2019-2020, were utilized. We calculated the mean and proportion changes in cardiovascular risk factors, and used linear and quadratic tests to assess the linear and nonlinear trends in their changes. Results: A total of 27891 participants aged 6 to 19-year-olds were included. Mean BMI increased significantly from 20.61kg/m 2 in 1999 to 21.71kg/m 2 in 2020 (P for trend < 0.001). COT means decreased from 11.47 ng/ml to 6.17 ng/ml (P for trend < 0.001). The prevalence of high COT decreased from 14.64% to 8.68% (P for trend < 0.001). TC decreased from 4.22mmol/L to 4.02 mmol/L (P for trend < 0.001). In the study population, TG levels decreased from 0.9mmol/L to 0.79 mmol/L (P for trend < 0.001). Mean LDL levels decreased from 2.45 mmol/L to 2.27 mmol/L (P for trend < 0.001). Conclusion: Positive trends were observed in the levels of TG, TC, LDL, and COT in US children and adolescents. Mean BMI and the prevalence of obesity exhibited a gradually increasing unfavorable trend.

Abstract 4117657: Targeting GPR39 for Hypoxia-induced Pulmonary Hypertension in Mice

Background: Primary pulmonary arterial hypertension (PAH) is a disease affecting young subjects. It has very poor prognosis and optimal treatment is not available. 15-hydroxyeicosatetraenoic acid (15-HETE), a potent vasoconstrictor, has been implicated in the pathogenesis of PAH. Elevated levels of 15-HETE have been shown to be associated with worse prognosis in patients with PAH. Oral ingestion of 15-HETE leads to development of PAH in rodents. We recently showed that 15-HETE is the endogenous agonist for the G-protein coupled receptor 39 (GPR39) present in vascular smooth muscle cells. Hypothesis: We, therefore, hypothesized that global deletion of GPR39 (knock-out [KO] mice) would protect from PAH by removing the receptor through which 15-HETE causes vasoconstriction. Methods: Accordingly, 13 wild-type (WT) and 16 KO mice were placed in a hypoxia chamber (10% O 2 ). Litter-mate controls (7 WT and 13 KO) were subjected to normoxia (room air, 21% O 2 ). At the end of 4 weeks heart rate as well as aortic and right ventricular (RV) pressures were measured (latter using micromanometer-tipped catheter), and the animals were then euthanized for measurement of RV wall thickness and RV size from which RV wall stress was calculated. Results: Heart rate and systolic blood pressure were not different between the 4 groups . WT hypoxic animals developed PAH with peak RV systolic pressures (RVSP) being significantly higher than normoxic WT and hypoxic WT and hypoxic KO mice. (Figure 1) Similar results were noted for RV end-diastolic pressure (Figure 2) and RV wall stress (Figure 3). Conclusions: By deleting GPR39, the target for 15-HETE, we were able to prevent hypoxia induced PAH and RV dysfunction. Pharmacological inhibition of GPR39 may open new frontiers in the treatment of PAH.

Abstract 4122694: The ICAM1 p.K56M Variant and Risk of Heart Failure Among Individuals with Chronic Kidney Disease

Background: Intercellular adhesion molecule-1 (ICAM-1) is a cell-surface protein that facilitates inflammation through leukocyte adhesion. Approximately 35% of African American individuals carry at least one copy of an ICAM1 missense variant (rs5491; p.K56M), which has been associated with increased risk of heart failure with preserved ejection fraction (HFpEF). Individuals with chronic kidney disease (CKD) are at high risk for HF, but whether the risk of HFpEF conferred by rs5491 extends to individuals with prevalent CKD is unknown. Hypothesis: We hypothesized that in a CKD population, rs5491 is specifically associated with HFpEF, but not HF with reduced ejection fraction (HFrEF). Methods: In the Chronic Renal Insufficiency Cohort (CRIC), participants were enrolled based upon an estimated glomerular filtration rate (eGFR) of 20 to 70 mL/min/1.73m 2 . We estimated associations of rs5491 with incident HF and HF subtypes among African American individuals who were free from HF at baseline in CRIC. Models were adjusted for age, sex, systolic blood pressure, eGFR, body mass index, smoking, diabetes, C-reactive protein, the first 10 principal components of ancestry, and study site. Results: Among 1267 African American participants without HF at baseline (mean age 57±11 years, 51% female, mean eGFR 45±15 mL/min/1.73m 2 ), 464 (37%) had at least one copy of rs5491. During a median follow-up of 10.3 years (IQR: 4.7 – 15.0 years), there were 309 incident overall HF hospitalizations (160 HFpEF, 111 HFrEF, and 38 HF with unknown EF). Each additional rs5491 allele was significantly associated with incident HFpEF (HR 1.35 [95% CI: 1.03-1.76], P=0.029; Figure). The rs5491 variant was not associated with incident overall HF (HR 1.14, 95% CI: 0.93-1.39, P = 0.20) or incident HFrEF (HR 0.76, 95% CI: 0.53-1.10, P=0.15). Conclusion: The ICAM1 p.K56M variant specifically confers increased risk of incident HFpEF among individuals with CKD.

Abstract 4125500: Obesity-Related Left Atrial Functional Change Becomes Apparent in Infancy

Background: Impaired left atrial (LA) function is observed in obese patients, however, there is little information on when LA dysfunction begins to appear. To clarify this issue, we assessed LA volume and function in obese infants. Methods: Two-dimensional speckle-tracking echocardiography was performed in 96 infants aged 4 months. Subjects were divided into 3 groups according to body mass index (BMI): normal (n=53), <17 kg/m 2 ; overweight (n=28), 17 to 19.9 kg/m 2 ; obese (n=15), ≧20 kg/m 2 . LA maximal volume, LA minimal volume, and LA pre-atrial contraction volume and LA longitudinal strain (reservoir, conduit, and booster) were measured. LA total emptying fraction, passive emptying fraction, and active emptying fraction were calculated. Results: Systolic blood pressure was significantly higher in the obese group than in the normal group (Table). LA maximal volume, minimal volume, and pre-atrial contraction volume increased significantly with increasing BMI (r = 0.53, 0.54, and 0.63, respectively, p <0.01). Compared with the normal group, reservoir LA strain was significantly lower in the overweight and obese groups. Conduit LA strain and passive emptying fraction were significantly lower in the overweight and obese groups than those in the normal group (Table). Reservoir LA strain, conduit LA strain, and passive emptying fraction decreased significantly with increasing BMI (r = -0.28, -0.27, and -0.33, respectively, p <0.01). There was no significant difference in booster LA strain among the 3 groups. Compared with the normal group, LA active emptying fraction was significantly higher in the obese group (Table). Conclusions: Higher BMI is associated with impaired reservoir and conduit LA function and higher booster LA pump function, which may be compensatory. Thus, obesity-related changes in LA functional begin to appear in infancy. Our data support prevention of obesity in early childhood because higher BMI is responsible for significant changes in LA function in early life.

Abstract 4135082: Small dense low-density lipoprotein cholesterol and risk of peripheral artery disease

Background: High levels of small dense low-density lipoprotein (sdLDL) is a hallmark of dyslipidemia; however, studies on sdLDL cholesterol levels and risk of peripheral artery disease are sparse and results inconclusive. Hypothesis: We tested the hypothesis that higher levels of sdLDL cholesterol are associated with increased risk of peripheral artery disease in a primary prevention setting. Methods: We studied 31,036 individuals free of lipid-lowering therapy, ischemic stroke, and myocardial infarction at study entry in 2013-2017. All had fresh sample measurements of sdLDL cholesterol. During a median follow-up on 6.2 years, 155 were diagnosed with peripheral artery disease. The association was confirmed using ankle-brachial index (ABI) ≤ 0.9 as endpoint. Lastly, as comparison across different vascular beds risk estimates for myocardial infarction and ischemic stroke were calculated. Results: Higher levels of sdLDL cholesterol were associated with higher risk of peripheral artery disease and an ABI ≤ 0.9 illustrated by cubic splines multivariable adjusted for sex, systolic blood pressure, education, body mass index (BMI), diabetes, large buoyant LDL cholesterol, and age. Per 1 mmol/L (37 mg/dL) higher sdLDL cholesterol hazard ratio for peripheral artery disease was 2.01 (95% CI: 1.41-2.85) and odds ratio for an ABI ≤ 0.9 was 1.51 (95% CI: 1.07-2.14) in multivariable adjusted models. The cumulative incidence of peripheral artery disease was respectively 1.5%, 2.5%, and 3.5% for individuals having a sdLDL cholesterol in the 1 st -50 th , 51 st -90 th , and the 91 st -100 th percentiles at age 80. For the 91 st -100 th versus the 1 st -50 th percentile a hazard ratio on 2.51 (95% CI: 1.50-4.20) for peripheral artery disease, 2.18 (95% CI: 1.58-3.01) for myocardial infarction, and 1.85 (95% CI: 1.37-2.49) for ischemic stroke was found. Furthermore, the association of higher sdLDL cholesterol with increased risk of peripheral artery disease was robust in sensitivity analyses. Conclusion: Higher levels of sdLDL cholesterol were robustly associated with increased risk of peripheral artery disease in a primary prevention setting.

Abstract 4141472: Birthweight is Associated with Left Ventricular Mass Index in Childhood

Introduction/Background: Increased left ventricular mass (LVM) is a risk factor for adult CV disease and is associated with cardiac development in utero. Associations of birthweight with LVM have been demonstrated in young children and adolescence, however, the association between birth weight and LVM in mid-childhood is not well described. Research Questions/Hypothesis: Utilizing an existing longitudinal data set of healthy children, we aimed to determine the association of birthweight to increased LVM at 6-8 years of age. Methods/Approach: A longitudinal cohort of 372 term-born children was enrolled at age 3 and followed until age 6-8 years. Anthropometrics, echocardiography, and maternal recall of birth weight were collected. LVM from echocardiography was indexed to height 2.7 . Multiple linear regression analysis was performed to assess the association of birthweight with LVM index at 6-8 years of age, adjusting for race, sex, body mass index (BMI) z-score, and systolic blood pressure (SBP) percentile collected at the time of echocardiography. Results: 303 children were included in the analysis (21.5% Black and 88.5% White, mean age 7.4 ± 0.3 years at the time of echocardiography, mean birthweight 3.4 ± 0.6 kg, mean SBP percentile 42.7 ± 21.6 percentile). Greater birthweight significantly contributed to greater LVM index (1.2 ± 0.6, p = 0.03), along with Black race (1.9 ± 0.8, p = 0.02) and greater current BMI z-score (2.1 ± 0.3, p < 0.01). Sex and SBP percentile were included in the model but were not significantly related to LVM index (p = 0.23 and 0.51 respectively) in this analysis. Conclusions: Greater birthweight is significantly associated with greater left ventricular mass in childhood, independent of BMI z-score at the time of echocardiography. This suggests a critical period in fetal cardiac development that affects cardiac structure in mid-childhood.

Abstract 4137914: Eligibility for Semaglutide in US Adults with Diabetes and Potentially Preventable Cardiovascular Events Projected from the SUSTAIN-6 Trial

Background: The Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN-6) trial showed cardiovascular disease (CVD) benefits of semaglutide therapy in patients with type 2 diabetes mellitus (T2DM). Purpose: To estimate the number of US adults with T2DM that may be eligible for semaglutide based on SUSTAIN-6 eligibility criteria and the number of preventable CVD events from semaglutide treatment based on observed CVD event reductions in SUSTAIN-6. Methods: We included US adults with T2DM from the National Health and Nutrition Examination Survey (NHANES) 2011– 2020 who had eligibility criteria from SUSTAIN-6. This included an HbA1c>7.0%, age > 50 with established CVD, heart failure, or chronic kidney disease or an age > 60 with at least one CVD risk factor. We estimated the number of primary composite and secondary CVD endpoints that would occur based on SUSTAIN-6 treated and placebo published event rates, with the difference indicating the number of preventable events (and annualized based on median 2.1 year follow-up time). Results: Among 5002 (projected to 34.0 million [M]) adults we identified with T2DM, we estimated 1,132 (6.9 million) (20.3%) to fit SUSTAIN-6 eligibility criteria. Compared to SUSTAIN-6 trial participants, our sample was slightly older, had a higher proportion of Black participants, shorter duration of diabetes, lower HbA1c and diastolic blood pressure, but similar body mass index and systolic blood pressure. Prior history of ischemic heart disease, myocardial infarction, and stroke were also less common in our NHANES sample. From SUSTAIN-6 semaglutide and placebo primary composite CVD event rates of 6.6% and 8.9%, respectively, we estimated 456,060 and 614,990 events would occur, respectively, for a total of 159,930 preventable CVD events, or 75,681 on an annualized basis. We similarly estimated annualized preventable events for secondary outcomes as shown in the Figure. Conclusion: Semaglutide may prevent many fatal and non-fatal CVD events if provided to US adults meeting SUSTAIN-6 eligibility criteria. More efforts are needed to educate the healthcare providers on the CVD benefits from newer diabetes therapies, including semaglutide.

Abstract 4137424: Circulating Levels of the Pro-Fibrotic Collagen Hormone Endotrophin are Associated with the Risk of Experiencing Major Adverse Cardiovascular Events in Individuals with Type 2 Diabetes – The Thousand&2 Study

Introduction: Cardiovascular disease (CVD) complications are the leading cause of mortality in individuals with type 2 diabetes (T2D). Abnormal extracellular matrix (ECM) remodelling leads to the release of ECM protein fragments into circulation, reflecting these complications. Endotrophin, a pro-fibrotic and -inflammatory hormone, released during collagen type 6 formation, has been linked to adverse outcomes in T2D, but not previously in a long-term perspective. Aim: To assess the 12-year prognostic value of circulating endotrophin levels, measured by PRO-C6, to predict the risk of major adverse cardiovascular events (MACE) in a large cohort of individuals with T2D. Methods: Endotrophin levels were measured with the NordicPRO-C6™ ELISA in 909 serum samples from the Thousand&2 study, which was initiated in 2011 and examined individuals with T2D, with and without known CVD. Clinical data were collected at baseline. Follow-up was 100% complete and performed on the 1 st of May 2024 with the registration of data on MACE from the Danish national registers. The primary outcome was MACE, defined as incident events of hospital admission for ischemic heart disease, heart failure, stroke, or all-cause mortality. PRO-C6 was split into tertiles and examined for survival probability by Kaplan-Meier analysis. Univariate Cox proportional hazard regression analysis was conducted to examine the association between PRO-C6 and the risk of MACE. A multivariable Cox model was additionally conducted, adjusted for age at baseline, sex, systolic blood pressure, duration of diabetes, HbA1c, estimated glomerular filtration rate, use of statins, albuminuria status, and current or prior smoking. Results: The baseline mean (±SD) age of the cohort was 64 (±10) years, 66% were males, mean (±SD) PRO-C6 was 11.9 (±7.01) ng/ml, the median follow-up time was 10.6 years, and number of MACE recorded was 472. The risk of experiencing MACE was significantly higher in the third tertile compared to the first and second tertile (Log-Rank p < 0.001). In the univariate Cox model, the estimated hazard ratio (HR), corresponding to a 2-fold increase of PRO-C6, was HR [95% Confidence Interval(CI)] = 2.1 [1.8-2.4], P <0.001. In the fully adjusted Cox model, PRO-C6 remained significantly associated with the risk of MACE (HR [95% CI] = 1.5 [1.2-1.8], P <0.001). Conclusion: Elevated circulating endotrophin is associated with MACE in T2D, independent of common risk factors.

Correlation between antihypertensive drugs and cerebral hemodynamic parameters: insights from observational findings using transcranial Doppler.

Antihypertensives (AHD) can influence cerebral autoregulation (CA) and attenuate hypertrophic concentric remodelling of arterioles. The aim of this study was to examine the associations between AHD, CA and structural and functional properties of cerebral arteries. In this observational, cross-sectional study 115 volunteers were divided in group 1 (non-hypertensive) [n = 30]; group 2 (hypertensive with systolic blood pressure [SBP] < 140 and diastolic blood pressure [DBP] < 90 mmHg) [n = 54]; group 3 (hypertensive with SBP ≥ 140 or DBP ≥ 90 mmHg) [n = 31] and simultaneous measurements of systemic blood pressure (BP) and middle cerebral artery blood flow velocity (CBFV) were obtained from digital plethysmography and transcranial Doppler. Beat-to-beat, critical closing pressure (CrCP), resistance-area product (RAP) and autoregulation index (ARI) values were extracted by linear regression analysis of instantaneous BP and CBFV waveforms using computerised analysis. Pulsatility index (PI) was calculated and CO2 reactivity was assessed by the breath-holding test. Despite their higher RAP (1.7 [±0.7], p < 0.001) compared to groups 1 and 2, uncontrolled hypertensive using diuretics (p = 0.047) and α2-agonists (p = 0.009) had significantly lower PI. Impaired CO2 reactivity was common between the two hypertensive groups (p = 0.008), however ARI, CrCP and CBFV did not differ between them and non-hypertensive individuals and also did not correlate with any AHD used. Unlike the RAP, PI does not seem to reflect the real cerebrovascular resistence resulting from chronic arterial remodelling. Despite impaired CO2 reactivity, hypertensivehavearterial tonus and CA comparable to non-hypertensive. Experimental studies involving an untreated hypertensive control group are required to robustly make definitive conclusions about these questions.

Abstract 4138716: A novel Urocortin-2 analog COR-1167 corrects cardiac and renal dysfunction on top of Empagliflozin in a rat model of acute decompensated heart failure

Introduction: Urocortin-2 (UCN-2) is a peptide belonging to the corticotropin-releasing factor family that has cardiovascular, renal, metabolic and anti-inflammatory actions and improves cardiac function in human heart failure (HF) and cardiorenal dysfunction in chronic HF models. However, UCN-2 has a short half-life and intravenous delivery limits its therapeutic use. COR-1167 was discovered as a stable UCN-2 analog with qd pharmacological effects when injected subcutaneously. Hypothesis: Whether COR-1167 exerts chronic cardiorenal protection in Acute Decompensated HF (ADHF) is unknown, and in particular on background of SGLT2 inhibition, therefore both treatments were tested in a rat model of ADHF. Methods: Rats had coronary artery ligation to induce MI and a reduced ejection fraction phenotype. Three months later, rats were treated with vehicle or Empagliflozin (Empa) at 10 mg/kg/day PO. One month after starting Empa, two acute decompensation events were induced by administrating NaCl solution (1.8 g/kg, PO) on Day 0 and Day 14. Empa treated ADHF rats received vehicle or COR-1167 (3 µg/kg/day) by SC injections starting at 12 hours after the first decompensation and all treatments continued for 14 days. The groups were ADHF, ADHF + Empa and ADHF + Empa + COR-1167 (n=7-10/group). Left ventricular (LV) hemodynamics (cardiac catheters), cardiac output (echocardiography) and LV tissue perfusion (magnetic resonance imaging), cardiac mitochondrial coupling and ATP production (Seahorse) were measured 1 day after the second decompensation, while urine volume (uVol) and urine Na + excretion (uNa + ) collected from metabolic cages were analyzed 7 days after the first decompensation. Results: Compared to ADHF control rats, Empa treatment had no effect on systolic blood pressure (SBP), cardiac output (CO), LV end systolic pressure volume relationship (LVESPVR), LV end diastolic pressure volume relationship (LVEDPR), mitochondrial coupling and ATP production, but it increased myocardial perfusion, uVol and uNa + excretion. Compared to ADHF + Empa rats, COR-1167 treatment increased SBP, CO, LVESPVR, myocardial perfusion, mitochondrial coupling and ATP production, uVol, uNa + , while decreasing LVEDPVR. Conclusion: In the setting of ADHF, significant cardiorenal benefits and decongestion occurred when COR-1167 was administered on top of an SGLT2 inhibitor.