Background:Prospective cohorts almost exclusively classified acute myocardial injury as a binary entity-presence or absence of myocardial infarction (MI). Objective:To compare Binary Classification of MI used in the Multi-Ethnic Study of Atherosclerosis (MESA) to an Etiological Classification of myocardial injury. Methods:Comparison of two different MI adjudication systems in 6809 participants aged 45-84 years old from MESA, a community-dwelling cohort free of cardiovascular disease at enrollment (2000). The Binary Classification defined events as MI versus "No MI". The Etiological Classification, based on the Fourth Universal Definition of MI, categorized events as MI (types 1-5), acute non-ischemic myocardial injury, chronic myocardial injury, and no myocardial injury. Number and distribution of myocardial infarction/injury events identified by each classification system were compared. Results:Binary Classification identified 333 MI events, while Etiological Classification identified 406 MIs, of which 202 (49.8%) were type 1 MI and 182 (44.8%) were type 2 MI, 22 (5.4%) were other MI types. Notably, 147 events (33 type 1 MI, 105 type 2 MI, 9 other MI types) were newly captured as MI with the Etiological Classification that were classified as No-MI by the Binary Classification. Among the 333 MI identified by the Binary Classification, 51% were type 1 MI (N = 169), 23% as type 2 MI (N = 77) and 17% as acute non-ischemic myocardial injury (N = 55) in the Etiological Classification. Conclusions:Etiological Classification identifies additional, etiologically distinct myocardial injury events. Almost half of the events identified as an MI by Binary Classification were identified as type 2 MI or acute non-ischemic myocardial injury by Etiological Classification.

BACKGROUND:We investigated whether circulating angiotensinogen levels are associated with the risk of ischemic stroke and examined sex-specific differences. METHODS:We included 5622 participants (mean age, 62.7 years; 52% women) free of cardiovascular disease at baseline (2000-2002) and followed them through 2020. Cox models assessed the association between angiotensinogen and ischemic stroke, including sex-stratified hazard ratios (HRs) with 95% CIs. Mediation analyses estimated the contribution of risk factors to observed associations. Subgroup analyses with multiplicative interaction testing were conducted. RESULTS:During follow-up, 283 ischemic stroke events occurred. Each 1-SD increase in log-transformed angiotensinogen was associated with a 16% higher stroke risk (HR, 1.16 [95% CI, 1.00-1.34]). Significant interaction with sex was observed (P interaction<0.001). In men, angiotensinogen showed a positive dose-response association with ischemic stroke (adjusted HR per SD increase, 1.71 [95% CI, 1.33-2.19]). Compared with the lowest tertile (<16.8 μg/mL), adjusted HRs were 1.68 (95% CI, 1.08-2.61) and 1.95 (95% CI, 1.26-3.03) for the second and third (>20 μg/mL) tertiles, respectively (P trend=0.004). Diabetes marginally mediated the association in men (proportion mediated, 0.04 [95% CI, 0.00-0.15]). Significant evidence of an association between angiotensinogen and ischemic stroke in women was not observed (HR, 1.07 [95% CI, 0.88-1.29] per SD). No significant multiplicative interactions were observed across subgroups defined by age, race, smoking status, diabetes, obesity, angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker use, hypertension, chronic kidney disease, and high-sensitivity C-reactive protein levels in either sex after Bonferroni correction (all P interaction>0.002). CONCLUSIONS:Higher circulating angiotensinogen levels are associated with an increased risk of ischemic stroke in men, independent of blood pressure.

AimsAngiotensinogen plays an essential role in maintaining circulatory homeostasis. AGT rs5050(T > G) has been identified as a regulator of the transcription of AGT mRNA, with differential expression between sexes. We sought to determine if rs5050(T > G), an estrogen response element, modifies the relationship between estrogen and angiotensinogen levels.Methodsrs5050(T > G) was genotyped, and plasma angiotensinogen levels were measured in 4,831 MESA participants, including postmenopausal women, on hormone therapy (n = 709) or not (n = 1,551), and 2,581 men. Linear regression models were employed to determine the associations of angiotensinogen with rs5050(T > G) allele dosage; and to evaluate whether rs5050(T > G) modifies the association between estradiol and angiotensinogen, with a main effect term and interaction term between rs5050(T > G)*estradiol. Estimated marginal means (EMMs) were used to further evaluate the effect of estradiol on angiotensinogen across different rs5050 alleles (T > G).Resultsrs5050TT had the highest median levels of angiotensinogen, followed by TG and GG. Adjusted main effect model showed positive associations between estradiol and angiotensinogen, with each rs5050T allele associated with 0.329 SD higher log-angiotensinogen levels (CI 95% 0.293, 0.365). The interaction rs5050(T > G)*estradiol was not significant, with EMMs exhibiting overlapping slope confidence intervals across genotypes. The proportion of the variance in angiotensinogen explained by modeling increases from 47.9% to 51.6% when including rs5050(T > G) or interation rs5050(T > G)*estradiol in the model.Conclusionsrs5050(T > G) is associated with circulating angiotensinogen levels, but rs5050(T > G) alleles do not influence the relationship between estradiol and angiotensinogen. This suggests that estrogen's effect on angiotensinogen regulation occurs independently of rs5050(T > G), despite its location within an estrogen-responsive element.

OBJECTIVE:The renin angiotensin aldosterone system plays a key role in circulatory homeostasis. We sought to identify genetic determinants of measured plasma angiotensinogen levels and subsequently evaluate the association of these single nucleotide polymorphisms (SNPs) with blood pressure (BP) and hypertension in a multiethnic population. METHODS:Genome-wide association study (GWAS) of plasma angiotensinogen levels, measured using an enzyme-linked immunoassay, was conducted in 4899 Multi-Ethnic Study of Atherosclerosis (MESA) participants (self-identified as White, n = 1865; Hispanic, n = 1113; Black, n = 1224; and Chinese, n = 629). Linear and logistic models examined the association between SNPs with angiotensinogen and hypertension, respectively. Mediation analysis evaluated the effect of angiotensinogen on BP/hypertension through the top SNPs identified by GWAS. RESULTS:In the analysis utilizing all participants, 115 SNPs were associated with angiotensinogen ( P < 5 × 10 -8 ), including lead SNP rs4762(G>A) in exon 2 ( P = 1.51E -100 ) and rs5050(T>G) in the promoter region ( P = 2.26E -69 ) of the AGT gene. Race/ethnic-specific analyses identified rs4762(G>A) as the lead SNP for White and Hispanic participants, whereas Black and Chinese participants had rs5050(T>G) and rs16852311(G>C), respectively. Both rs4762(G>A) and rs5050(T>G) indirectly increased systolic BP, diastolic BP, and the odds of hypertension through its effect of increasing angiotensinogen. CONCLUSIONS:Our findings demonstrate racial/ethnic differences in genetic effects on angiotensinogen levels across multiple SNPs. AGT rs4762(G>A) and rs5050(T>G) impact BP and hypertension through a mediated effect via angiotensinogen, though opposing direct effects may mask the overall association.

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 Effective therapies for reducing cardiovascular disease (CVD) risk in people with elevated lipoprotein(a) are lacking, especially for primary prevention. Because of the potential association of lipoprotein(a) with thrombosis, we evaluated the relationship between aspirin use and CVD events in people with elevated lipoprotein(a). Methods and Results We used data from the MESA (Multi‐Ethnic Study of Atherosclerosis), a prospective cohort study of individuals free of baseline cardiovascular disease. Due to potential confounding by indication, we matched aspirin users to nonusers using a propensity score based on CVD risk factors. We then evaluated the association between aspirin use and coronary heart disease (CHD) events (CHD death, nonfatal myocardial infarction) stratified by baseline lipoprotein(a) level (threshold of 50 mg/dL) using Cox proportional hazards models with adjustment for CVD risk factors. After propensity matching, the study cohort included 2183 participants, including 1234 (57%) with baseline aspirin use and 423 (19%) with lipoprotein(a) >50 mg/dL. Participants with lipoprotein(a) >50 mg/dL had a higher burden of CVD risk factors, more frequent aspirin use (61.7% versus 55.3%, P=0.02), and higher rate of incident CHD events (13.7% versus 8.9%, P<0.01). Aspirin was associated with a significant reduction in CHD events among those with elevated lipoprotein(a) (hazard ratio, 0.54 [95% CI, 0.32–0.94]; P=0.03). Those with lipoprotein(a) >50 mg/dL and aspirin use had similar CHD risk as those with lipoprotein(a) ≤50 mg/dL regardless of aspirin use. Conclusions Aspirin use was associated with a significantly lower risk for CHD events in participants with lipoprotein(a) >50 mg/dL without baseline CVD. The results of this observational propensity‐matched study require confirmation in studies with randomization of aspirin use.

Background and aimsWith the advent and implementation of high-sensitivity cardiac troponin assays, differentiation of patients with distinct types of myocardial injuries, including acute thrombotic myocardial infarction (TMI), acute non-thrombotic myocardial injury (nTMi), and chronic coronary atherosclerotic disease (cCAD), is of pressing clinical importance. Thermal liquid biopsy (TLB) emerges as a valuable diagnostic tool, relying on identifying thermally induced conformational changes of biomolecules in blood plasma. While TLB has proven useful in detecting and monitoring several cancers and autoimmune diseases, its application in cardiovascular diseases remains unexplored. In this proof-of-concept study, we sought to determine and characterize TLB profiles in patients with TMI, nTMi, and cCAD at multiple acute-phase time points (T 0 h, T 2 h, T 4 h, T 24 h, T 48 h) as well as a follow-up time point (Tfu) when the patient was in a stable state.MethodsTLB profiles were collected for 115 patients (60 with TMI, 35 with nTMi, and 20 with cCAD) who underwent coronary angiography at the event presentation and had subsequent follow-up. Medical history, physical, electrocardiographic, histological, biochemical, and angiographic data were gathered through medical records, standardized patient interviews, and core laboratory measurements.ResultsDistinctive signatures were noted in the median TLB profiles across the three patient types. TLB profiles for TMI and nTMi patients exhibited gradual changes from T0 to Tfu, with significant differences during the acute and quiescent phases. During the quiescent phase, all three patient types demonstrated similar TLB signatures. An unsupervised clustering analysis revealed a unique TLB signature for the patients with TMI. TLB metrics generated from specific features of TLB profiles were tested for differences between patient groups. The first moment temperature (TFM) metric distinguished all three groups at time of presentation (T0). In addition, 13 other TLB-derived metrics were shown to have distinct distributions between patients with TMI and those with cCAD.ConclusionOur findings demonstrated the use of TLB as a sensitive and data-rich technique to be explored in cardiovascular diseases, thus providing valuable insight into acute myocardial injury events.

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 AND AIMS:Although several biomarkers have been studied in thromboembolic stroke, measuring the balance between thrombus formation and thrombolysis and data on its role in predicting stroke and atrial fibrillation (AF)-related stroke is limited. We sought to assess atherothrombotic biomarkers grouped into composite factors that reflect thrombotic and thrombolytic potential, and the balance between these factors as it relates to incident stroke or transient ischemic attack (TIA) and stroke/TIA in AF. METHODS:A Thrombotic Factor, derived from fibrinogen, plasmin-antiplasmin complex, factor VIII, D-dimer, and lipoprotein(a); and a Thrombolytic Factor, derived from plasminogen and oxidized phospholipids on plasminogen, were evaluated at baseline in 5,764 Multi-Ethnic Study of Atherosclerosis (MESA) participants. We evaluated the association between these two factors representative of thrombotic and thrombolytic potential and incident stroke/TIA (n = 402), and AF-related stroke/TIA (n = 82) over a median of 13.9 and 3.7 years, respectively. Cox proportional hazard models adjusted for medication use, cardiovascular risk factors and CHA2DS2-VASc score were utilized. Harrell's C-index was estimated to evaluate model performance. RESULTS:In models including both factors, Thrombotic Factor was positively while Thrombolytic Factor was inversely associated with incident stroke/TIA and AF-related stroke/TIA. Incorporating these factors along with the CHA2DS2-VASc in adjusted models resulted in a small improvement in risk prediction of incident stroke/TIA and AF-related stroke/TIA compared to models without the factors (C-index from 0.697 to 0.704, and from 0.657 to 0.675, respectively). CONCLUSIONS:Composite biomarker factors, representative of the balance between thrombotic and thrombolytic propensity, provided an improvement in predicting stroke/TIA beyond CHA2DS2-VASc score.

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.

Phytophthora blight, caused by Phytophthora capsici, is a serious disease of many vegetable crops worldwide. In New Mexico, U.S.A., the disease affects chile pepper (Capsicum annuum L.), a major crop in the state. There is no single tool that effectively controls the disease. Continuous research is needed in identifying combination of tools that can reduce the impact of Phytophthora blight. We explored the potential of combining cover crops and biocontrol agents to reduce soilborne diseases. This study aimed to evaluate the effects of Indian mustard (Brassica juncea L.) cover crop on the antagonistic ability of Trichoderma harzianum against P. capsici in vitro and to quantify the impacts of combining soil amendment with residues from B. juncea and barley (Hordeum vulgare L.) cover crops and plastic covering on infection of chile pepper seedlings by P. capsici under greenhouse conditions. Volatiles from macerated tissue of B. juncea significantly reduced P. capsici and T. harzianum growth in the absence of soil by 89.0 and 79.0%, respectively. When incorporated in soils, volatiles from macerated tissue of B. juncea significantly reduced P. capsici and T. harzianum by 33.4 and 7.8%, respectively. T. harzianum was more resilient to B. juncea biofumigation than P. capsici. Significant reduction in disease incidence was observed with B. juncea-fumigated soil, while no disease suppression was observed with soil incorporation of H. vulgare residues. Covering soil with plastic was necessary for increasing the efficacy of B. juncea biofumigation.

Background Despite different prevalence, pathobiology, and prognosis between etiologically distinct myocardial infarction (MI) subtypes, prospective study of risk factor for MI in large NHLBI-sponsored cardiovascular cohorts is limited to acute MI as a singular entity. Therefore, we sought to utilize the Multi-Ethnic Study of Atherosclerosis (MESA), a large prospective primary prevention cardiovascular study, to define the incidence and risk factor profile of individual myocardial injury subtypes.Methods We describe the rationale and design of re-adjudicating 4,080 events that occurred over the first 14 years of follow-up in MESA for the presence and subtype of myocardial injury as defined by the Fourth Universal Definition of MI: MI type 1 to 5, acute non-ischemic myocardial injury, and chronic myocardial injury. The project utilizes a 2-physician adjudication process via examination of medical records, abstracted data collection forms, cardiac biomarker results, and electrocardiograms of all relevant clinical events. Comparison of the magnitude and direction of associations between base-line traditional and novel cardiovascular risk factors with incident and recurrent acute MI subtypes and acute non-ischemic myocardial injury events will be made.Conclusions This project will result in one of the first large prospective cardiovascular cohort with modern classification of acute MI subtypes, as well as a full accounting of non-ischemic myocardial injury events, with implications for numerous ongoing and future studies in MESA. By creating precise MI phenotypes, and defining their epidemiology, this project will allow for discovery of novel pathobiology-specific risk factors, allow for development of more accurate risk prediction, and suggest more targeted preventive strategies. (Am Heart J 2023;260:151-173.)

BACKGROUND Angiotensinogen is the proximal precursor of the angiotensin peptide hormones of the renin-angiotensin-aldosterone system (RAAS). Clinical trials are ongoing targeting angiotensinogen for the treatment of hy-pertension and heart failure. The epidemiology of angiotensinogen is not well defined, particularly its relationship to ethnicity, sex, and blood pressure (BP)/hypertension. OBJECTIVES The authors sought to determine the relationship of circulating angiotensinogen levels to ethnicity, sex, BP, incident hypertension, and prevalent hypertension in a modern sex-balanced ethnically diverse cohort.METHODS Plasma angiotensinogen levels were measured in 5,786 participants from the MESA (Multi-Ethnic Study of Atherosclerosis). Linear, logistic, and Cox proportional hazards models were utilized to examine the associations of angiotensinogen with BP, prevalent hypertension, and incident hypertension, respectively.RESULTS Angiotensinogen levels were significantly higher in females than males and differed across self-reported ethnicities with the ordering (from highest to lowest): White, Black, Hispanic, and Chinese adults. Higher levels were associated with higher BP and odds of prevalent hypertension, after adjusting for other risk factors. Equivalent relative differences in angiotensinogen were associated with greater differences in BP in males vs females. In males not taking RAAS-blocking medications, a standard deviation increment in log-angiotensinogen was associated with 2.61 mm Hg higher systolic BP (95% CI: 1.49-3.80), while in females the same increment in angiotensinogen was associated with 0.97 mm Hg higher systolic BP (95% CI: 0.30-1.65).CONCLUSIONS Significant differences in angiotensinogen levels are present between sexes and ethnicities. A positive association is present between levels and prevalent hypertension and BP, which differs between sexes. (J Am Coll Cardiol 2023;81:1248-1259) (c) 2023 by the American College of Cardiology Foundation.

Introduction: There is a lack of effective therapies for reducing risk in people with elevated Lp(a), especially for primary prevention. We aimed to evaluate the association between aspirin use and cardiovascular events (CVD) in people with elevated Lp(a). Methods: We performed a prospective cohort study using data from participants from the Multi-Ethnic Study of Atherosclerosis (MESA) who were free of baseline cardiovascular disease. We matched aspirin users and non-users using a propensity score based on CVD risk factors. We then evaluated the association between aspirin use and coronary heart disease (CHD) events (CHD death, non-fatal myocardial infarction) stratified by baseline Lp(a) level (above and below 50 mg/dL) using Cox proportional hazards models with adjustment for CVD risk factors. Results: Our study cohort included 6,632 participants, including 1,138 (20%) with Lp(a) >50 mg/dL and 1,592 (24%) with baseline aspirin use. Participants with elevated Lp(a) had a higher burden of CVD risk factors, with a trend toward greater aspirin use (25.7% vs 23.6%, p=0.10) and significantly higher CHD events (9.0% vs 7.3%, p=0.03). After propensity matching, aspirin was associated with a significant reduction in CHD events among those with elevated Lp(a) (HR 0.54, 95% CI 0.32-0.94, p=0.03). Those with Lp(a) >50 mg/dL with aspirin use had similar freedom from CHD as those with Lp(a) ≤50 mg/dL regardless of aspirin use ( Figure ). Conclusions: Aspirin use was associated with a significant reduction in CHD events in participants with elevated Lp(a) without baseline CVD. These results are hypothesis generating and require confirmation in studies with randomization of aspirin use.

The renin-angiotensin-aldosterone system (RAAS) is a well-defined pathway playing a key role in maintaining circulatory homeostasis. Abnormal activation of RAAS contributes to development of cardiovascular disease, including heart failure, cardiac hypertrophy, hypertension, and atherosclerosis. Although several key RAAS enzymes and peptide hormones have been thoroughly investigated, the role of angiotensinogen—the precursor substrate of the RAAS pathway—remains less understood. The study of angiotensinogen single-nucleotide polymorphisms (SNPs) has provided insight into associations between angiotensinogen and hypertension, congestive heart failure, and atherosclerotic cardiovascular disease. Targeted drug therapy of RAAS has dramatically improved clinical outcomes for patients with heart failure, myocardial infarction, and hypertension. However, all such therapeutics block RAAS components downstream of angiotensinogen and elicit compensatory pathways that limit their therapeutic efficacy as monotherapy. Upstream RAAS targeting by an angiotensinogen inhibitor has the potential to be more efficacious in patients with suboptimal RAAS inhibition and has a better safety profile than multiagent RAAS blockade. Newly developed therapeutics that target angiotensinogen through antisense oligonucleotides or silencer RNA technologies are providing a novel perspective into the pathobiology of angiotensinogen and show promise as the next frontier in the treatment of cardiovascular disease.