Angiotensinogen, the unique precursor of all angiotensin hormones of the renin-angiotensin-aldosterone system (RAAS), is now a potential target in a novel pharmacological approach to hypertension. Investigating the factors that influence angiotensinogen levels, including sex hormones, may have important therapeutic implications. Plasma angiotensinogen and sex hormones levels were measured in 5171 Multi-Ethnic Study of Atherosclerosis (MESA) participants. Linear models were employed to determine the associations of angiotensinogen with sex hormones. Angiotensinogen levels were significantly higher in postmenopausal women receiving hormone therapy (HT, n = 760) compared to women not receiving HT (n = 1675) and in men (n = 2736). A positive association was present between angiotensinogen and estrogen levels that differed in magnitude between sexes and by HT status among postmenopausal women (women on HT: r = 0.44, p < 0.0001; women not on HT: r = 0.09, p = 0.0002; and men: r = 0.07, p = 0.0003). The type of HT formulation (estrogen or estrogen/progesterone) and its duration of use did not significantly affect angiotensinogen levels. This study suggests a significant role of sex, estrogen, and HT in the pathophysiology of angiotensinogen, which is important given the development and testing of angiotensinogen-targeting therapeutics.

Background: The distinction between thrombotic myocardial infarction (TMI) and non-thrombotic myocardial injury (nTMi) is crucial, given their varied etiologies, unique treatment approaches, and higher misclassification in clinical setting. In this study, we compared plasma proteome among individuals with TMI, nTMi, and chronic coronary artery disease (cCAD). Methods: Mass spectrometry-based proteomic analysis was conducted in 173 patients (84 with TMI, 36 with nTMi, and 51 with cCAD) who underwent coronary angiography (T 0 - acute time) and had an average 3-month post-procedure follow-up (T fu, quiescent state). Initially, we assessed temporal change from T 0 to T fu in proteomic profile in TMI group to identify proteins elevated during acute thrombosis. Subsequently, we compared these proteins’ levels at the acute phase across all groups to find differentially expressed proteins. We used hierarchical Bayesian models to analyze protein abundances, considering study group, time-point, and their interaction, with random effects for individual variability. Statistical significance was determined using Bayesian factor analysis with a threshold of BF > 150. Results: Proteomic profiling of plasma samples quantified 1,756 proteins. In TMI, 141 proteins varied significantly between T 0 and T fu . Proteins related to platelet activation, hemostasis, cell adhesion, and tissue remodeling were elevated. In contrast, proteins associated with extracellular matrix remodeling, cell adhesion, receptor signaling, and growth factor binding were reduced. Notably, six proteins showed differences when comparing TMI to nTMi. Specifically, Decorin, Myoglobin, and C-reactive protein levels were elevated during T 0 , while the others were decreased in TMI group. Comparing TMI to cCAD, 47 proteins differed significantly ( Figure 1A ). Conclusion: Our unique study design, using patients as their own controls, helped us in identifying distinct proteomic signature that can offers a promising set of noninvasive biomarkers for differentiating between TMI from other myocardial injury events.

Background: With demographic trends transitioning towards older adults, dementia and cognitive impairment are predicted to increase dramatically. We aim to elucidate the relationship between subclinical myocardial injury, as indicated by asymptomatic increased levels of high-sensitivity cardiac Troponin (hs-cTnT), and cognitive performance. Methods: We studied MESA participants from Exam 1 (2000-02) to Exam 6 (2016-18), categorizing them based on baseline hs-cTnT at Exam 1. Cognitive decline was defined as a decrease of ≥5 units in CASI between Exam 5&6. We used Pearson correlation and linear regression to analyze the association of hs-cTnT levels with CASI scores, and logistic regression to examine the association with cognitive decline. We also explored the relationship between different hs-cTnT categories and cognitive measures. Models were adjusted for demographics, lifestyle, APOE status, comorbidities, and medication use ( Figure ). Results: 4445 participants had both baseline hs-cTnT and valid Exam 5 CASI scores while only 1776 participants had valid Exam 6 CASI scores. Cohort was predominantly female (53%), mean age of 60 years, and 27% had at least one APOE e4 allele. Median hs-cTnT was 6.32 ng/L, and median CASI scores were 89 at Exam 5 and 91.5 at Exam 6. We found a negative correlation between the log-hs-cTnT at Exam 1 and Exam 5 with CASI scores at Exam 5. An increase of one unit in log-hs-cTnT level was associated with a decrease of 0.67 (CI -1.17, -0.17) in CASI and corresponded to higher odds (OR: 1.44; CI 1.05-1.95) of cognitive decline, after adjusting for covariates. When comparing various categories of hs-cTnT with category 1, we observe that the odd of cognitive decline increases as the category increases. However, this trend does not hold for category 5 with significantly lower sample size ( Figure ). Conclusion: Our findings indicate an inverse relationship between hs-cTnT and cognitive function years later, which is significantly attenuated by known risk factors for cognitive decline. Further research is needed to determine hs-cTnT as a predictor of future global cognitive functions.

Background: Chagas disease (CD) is an infectious disease caused by the protozoa Trypanosoma cruzi , affecting around 6-7 million people in Latin America. Although most infected individuals remain asymptomatic throughout their lives, annually 2-5% of them progress to chronic chagasic cardiomyopathy (CCC), digestive megasyndromes, or both. Ficolins are innate immunity proteins that play a crucial role in the lectin pathway (LP) of complement activation. They recognize pathogen-associated molecular patterns and mediate the clearance of apoptotic cells and cellular debris. Genetic polymorphisms of components of LP have been associated with clinical forms of CD; however, the relationship between Ficolin-1 ( FCN1 ) gene polymorphisms and CD remains unclear. Hypothesis: We hypothesize that polymorphisms in the FCN1 gene, previously related to its expression, are associated with clinical forms of CD, possibly impacting LP activation. Goals: To investigate the association of genetic variants of the FCN1 gene with the clinical forms of chronic CD. Methods: We evaluated three single-nucleotide polymorphisms (SNPs): rs2989727G>A (c.-1981G>A), rs17039495 (-399G>A) and rs10858293 (+33G>T) by sequence-specific amplification in 200 patients with chronic CD (23.5% asymptomatic, 52% CCC, 10% digestive form, and 14.5% cardiodigestive form) from Southern Brazil, and 210 T. cruzi seronegative controls. Logistic regression models were adjusted for sex, age, and self-identified ethnicity, followed by Bonferroni correction. Results: The haplotypes GGG, AGT, AGG, GAT, and AAT were more frequently found in patients, while GGG, AGT, AGG, and AAT were more common in controls. We observed a higher frequency of the G allele (p=0.004; OR 1.49; 95% CI 1.14, 1.99) of SNP rs2989727 and the GG genotype (p=0.010; OR 1.82; 95% CI 1.10, 3.03) in CD patients, particularly those with symptomatic forms (p=0.008; OR 1.51; 95% CI 1.11, 2.03; and p=0.012; OR 2.05; 95% CI 1.17, 3.59) and CCC (p=0.013; OR 1.54; 95% CI 1.10, 2.16, and p=0.013; OR 2.16; 95% CI 1.18, 3.97), compared to the control group. Conclusion: The FCN1 rs2989727 variant is associated with chronic CD and CCC, likely due to its impact on FCN1 gene expression.

Background: Emergency department (ED) overcrowding is a significant healthcare challenge that continues to strain medical facilities internationally. The need to assess myocardial injury in the ED is thought to be common, accounting for greater than 13 million visits annually. Therefore, we sought to assess the frequency and impact of myocardial injury assessment on the intermediates to ED overcrowding – ED disposition distribution and time to disposition – at an urban ED. Methods: In this single-center, retrospective cohort study from February 1, 2023, to January 31, 2024, the disposition distribution and median time to disposition were recorded for ED patient encounters. The study population was divided into encounters resulting in ED assessment for myocardial injury with conventional troponin measurement (ED-Tn group) and all other encounters without ED assessment for myocardial injury (control group). Pearson test was used for analyzing disposition distribution and Wilcoxon test for comparing time to disposition between the two defined groups. Results: 66,984 patient encounters resulted in a disposition of discharge or admission during the study period. 15,918 (23.8%) were categorized into ED-Tn group, while 51,066 (76.2%) were categorized into control group. The ED-Tn group had a significantly lower discharge frequency of 51% compared to the control group with 59.1% (p<0.001). The median time to disposition was significantly higher for the ED Tn group at 212 minutes (IQR = 124, 325) compared to the control group at 184 minutes (IQR = 95, 313; p<0.001). When considering only those patients who were discharged from the ED, the difference in median time to disposition was even more pronounced for the ED-Tn group at 226 minutes (IQR = 139, 340) compared to the control group at 178 minutes (IQR = 86, 311; p<0.001). Conclusions: In an urban ED, myocardial injury assessments comprised a quarter of all ED evaluations, linked to increased admission and extended time to disposition for these patients. Implementing high-sensitivity troponin could improve efficiency of ED assessment for myocardial injury and alleviate overcrowding, given the resource-intensive and time-intensive nature of these assessments.

Background: The 4th Universal Definition of Myocardial Injury (UDMI) recognizes several categories of myocardial injury, including acute myocardial infarction (MI) which is further sub-classified into five types. However, data on these different types of myocardial injury and their risk factors is limited. Methods: In the MESA study of 6814 participants, 15905 clinical events were identified over the first 14 years, 4079 of which meet MESA criteria for physician adjudication for a possible cardiovascular event. Herein, we developed a standardized data format and a REDCap tool with an interactive robust logic algorithm to re-adjudicate all 4079 cases for the presence and classification of all 9 types of myocardial injury as defined by the 4 th UDMI. Adjudication process as shown in Figure 1 . The prevalence of myocardial injury types was evaluated using descriptive statistics, and adjudicator agreement was assessed using Cohen’s kappa (κ) statistics and percent agreement. Results: Out of 4079 events, adjudication is completed on 2282, of which 15% classified into subtypes of myocardial injury. Adjudication was achieved for 91% of the events in phase 1, 7% in phase 2, 2% in phase 3. The overall agreement between two adjudicators for the presence of myocardial injury was 91% (κ: 0.67), but the agreement for the specific subtype was 53% (κ: 0.38). The most common events were Type 1 MI (N= 114), followed by Type 2 MI (N= 95), and Acute non-ischemic myocardial injury (N= 85) ( Figure 2 ). Compared to the original MESA adjudication for the presence of MI, 97% (N= 72) of probable MI and 8% (N= 174) of no MI were reclassified into five and six types of myocardial injury events respectively. Conclusion: This study highlights the complexities in identifying subtypes of myocardial injury based on current definition. This study provides a novel dataset to explore diverse correlations with these myocardial injury subtypes.

BACKGROUND Oxidized phospholipids (OxPLs) are carried by apolipoprotein B-100-containing lipoproteins (OxPL-apoB) including lipoprotein(a) (Lp[a]). Both OxPL-apoB and Lp(a) have been associated with calcific aortic valve disease (CAVD). OBJECTIVES This study aimed to evaluate the associations between OxPL-apoB, Lp(a) and the prevalence, incidence, and progression of CAVD. METHODS OxPL-apoB and Lp(a) were evaluated in MESA (Multi-Ethnic Study of Atherosclerosis) and a participant-level meta-analysis of 4 randomized trials of participants with established aortic stenosis (AS). In MESA, the association of OxPL-apoB and Lp(a) with aortic valve calcium (AVC) at baseline and 9.5 years was evaluated using multivariable ordinal regression models. In the meta-analysis, the association between OxPL-apoB and Lp(a) with AS progression (annualized change in peak aortic valve jet velocity) was evaluated using multivariable linear regression models. RESULTS In MESA, both OxPL-apoB and Lp(a) were associated with prevalent AVC (OR per SD: 1.19 [95% CI: 1.07-1.32] and 1.13 [95% CI: 1.01-1.27], respectively) with a significant interaction between the two (P < 0.01). Both OxPL-apoB and Lp(a) were associated with incident AVC at 9.5 years when evaluated individually (interaction P < 0.01). The OxPL-apoB & lowast;Lp(a) interaction demonstrated higher odds of prevalent and incident AVC for OxPL-apoB with increasing Lp(a) levels. In the meta-analysis, when analyzed separately, both OxPL-apoB and Lp(a) were associated with faster increase in peak aortic valve jet velocity, but when evaluated together, only OxPL-apoB remained significant (ss: 0.07; 95% CI: 0.01-0.12). CONCLUSIONS OxPL-apoB is a predictor of the presence, incidence, and progression of AVC and established AS, particularly in the setting of elevated Lp(a) levels, and may represent a novel therapeutic target for CAVD. (c) 2024 by the American College of Cardiology Foundation.

Background: The renin angiotensin aldosterone system (RAAS) is crucial for circulatory homeostasis and multiple cardiovascular diseases. Despite research on key RAAS components, resulting in multiple therapeutics, the role of angiotensinogen, the sole substrate, remains less understood. We sought to elucidate the relationship between circulating angiotensinogen levels and single nucleotide polymorphisms (SNPs) in a multi-ethnic cohort study. Methods: Genome-wide association analyses of plasma angiotensinogen levels were conducted in 4,899 MESA participants (self-identified as White, n=1,868; Hispanic, n=1,115; Black, n=1,283; and Chinese, n=633). Plasma angiotensinogen levels were measured at the baseline using an enzyme-linked immunoassay. Linear models were adjusted for age, sex, comorbidities, and sex hormones, along with top principal components to account for population structure. Furthermore, we conducted conditional analysis identifying SNPs meeting genome-wide significance for population-specific associations conditioned on the lead SNP in each race/ethnicity. Results: We identified 115 SNPs associated with angiotensinogen levels (p< 5×10 −8 ), including the lead SNP rs4762 (Thr174Met) in exon 2 (β=-0.159, p=1.51E -100 ) and SNP rs5050 (A-20C) in the promoter region (β=-0.109, p=2.26E -69 ) within the AGT gene. Strong Linkage Disequilibrium [LD (r 2 >0.8)] was observed between rs4762 and rs35837081 for White, Black, and Hispanic ethnicities. Conversely, this level of LD was noted between rs4762 and rs3789657 specifically within Chinese. The LD between rs4762 and rs5050 was higher for White (r 2 =0.65), followed by Chinese (r 2 =0.56), Hispanic (r 2 =0.55), and Black (r 2 =0.29). Conditioned on rs4762 in the White population, we identified four secondary signals associated with angiotensinogen including rs2493151 (β=0.053, p=4.08E -9 ), implicated in transcription factor binding. Measured angiotensinogen levels were 9.7%, 12.8%, and 17.3% lower in Black, Hispanic, and Chinese, respectively, compared to White participants. Conclusions: These findings extend angiotensinogen research, highlighting the SNPs rs4762 and rs5050 as the key variants associated with angiotensinogen levels, both previously linked to hypertension.