Characterization of myocardial injury phenotype by thermal liquid biopsy.

Background and aims: With 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. Methods: TLB 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. Results: Distinctive 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. Conclusion: Our 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.

Prognostic performance of the IABP-SHOCK II Risk Score among cardiogenic shock subtypes in the critical care cardiology trials network registry.

BACKGROUND: Risk stratification has potential to guide triage and decision-making in cardiogenic shock (CS). We assessed the prognostic performance of the IABP-SHOCK II score, derived in Europe for acute myocardial infarct-related CS (AMI-CS), in a contemporary North American cohort, including different CS phenotypes. METHODS: The critical care cardiology trials network (CCCTN) coordinated by the TIMI study group is a multicenter network of cardiac intensive care units (CICU). Participating centers annually contribute ≥2 months of consecutive medical CICU admissions. The IABP-SHOCK II risk score includes age > 73 years, prior stroke, admission glucose > 191 mg/dl, creatinine > 1.5 mg/dl, lactate > 5 mmol/l, and post-PCI TIMI flow grade < 3. We assessed the risk score across various CS etiologies. RESULTS: Of 17,852 medical CICU admissions 5,340 patients across 35 sites were admitted with CS. In patients with AMI-CS (n = 912), the IABP-SHOCK II score predicted a >3-fold gradient in in-hospital mortality (low risk = 26.5%, intermediate risk = 52.2%, high risk = 77.5%, P < .0001; c-statistic = 0.67; Hosmer-Lemeshow P = .79). The score showed a similar gradient of in-hospital mortality in patients with non-AMI-related CS (n = 2,517, P < .0001) and mixed shock (n = 923, P < .001), as well as in left ventricular (<0.0001), right ventricular (P = .0163) or biventricular (<0.0001) CS. The correlation between the IABP-SHOCK II score and SOFA was moderate (r2 = 0.17) and the IABP-SHOCK II score revealed a significant risk gradient within each SCAI stage. CONCLUSIONS: In an unselected international multicenter registry of patients admitted with CS, the IABP- SHOCK II score only moderately predicted in-hospital mortality in a broad population of CS regardless of etiology or irrespective of right, left, or bi-ventricular involvement.

Optimal Screening for Predicting and Preventing the Risk of Heart Failure Among Adults With Diabetes Without Atherosclerotic Cardiovascular Disease: A Pooled Cohort Analysis.

BACKGROUND: The optimal approach to identify individuals with diabetes who are at a high risk for developing heart failure (HF) to inform implementation of preventive therapies is unknown, especially in those without atherosclerotic cardiovascular disease (ASCVD). METHODS: Adults with diabetes and no HF at baseline from 7 community-based cohorts were included. Participants without ASCVD who were at high risk for developing HF were identified using 1-step screening strategies: risk score (WATCH-DM [Weight, Age, Hypertension, Creatinine, HDL-C, Diabetes Control, QRS Duration, MI, and CABG] ≥12), NT-proBNP (N-terminal pro-B-type natriuretic peptide ≥125 pg/mL), hs-cTn (high-sensitivity cardiac troponin T ≥14 ng/L; hs-cTnI ≥31 ng/L), and echocardiography-based diabetic cardiomyopathy (echo-DbCM; left atrial enlargement, left ventricular hypertrophy, or diastolic dysfunction). High-risk participants were also identified using 2-step screening strategies with a second test to identify residual risk among those deemed low risk by the first test: WATCH-DM/NT-proBNP, NT-proBNP/hs-cTn, NT-proBNP/echo-DbCM. Across screening strategies, the proportion of HF events identified, 5-year number needed to treat and number needed to screen to prevent 1 HF event with an SGLT2i (sodium-glucose cotransporter 2 inhibitor) among high-risk participants, and cost of screening were estimated. RESULTS: The initial study cohort included 6293 participants (48.2% women), of whom 77.7% without prevalent ASCVD were evaluated with different HF screening strategies. At 5-year follow-up, 6.2% of participants without ASCVD developed incident HF. The 5-year number needed to treat to prevent 1 HF event with an SGLT2i among participants without ASCVD was 43 (95% CI, 29-72). In the cohort without ASCVD, high-risk participants identified using 1-step screening strategies had a low 5-year number needed to treat (22 for NT-proBNP to 37 for echo-DbCM). However, a substantial proportion of HF events occurred among participants identified as low risk using 1-step screening approaches (29% for echo-DbCM to 47% for hs-cTn). Two-step screening strategies captured most HF events (75-89%) in the high-risk subgroup with a comparable 5-year number needed to treat as the 1-step screening approaches (30-32). The 5-year number needed to screen to prevent 1 HF event was similar across 2-step screening strategies (45-61). However, the number of tests and associated costs were lowest for WATCH-DM/NT-proBNP ($1061) compared with other 2-step screening strategies (NT-proBNP/hs-cTn: $2894; NT-proBNP/echo-DbCM: $16 358). CONCLUSIONS: Selective NT-proBNP testing based on the WATCH-DM score efficiently identified a high-risk primary prevention population with diabetes expected to derive marked absolute benefits from SGLT2i to prevent HF.

Restrictive or Liberal Transfusion Strategy in Myocardial Infarction and Anemia.

BACKGROUND: A strategy of administering a transfusion only when the hemoglobin level falls below 7 or 8 g per deciliter has been widely adopted. However, patients with acute myocardial infarction may benefit from a higher hemoglobin level. METHODS: In this phase 3, interventional trial, we randomly assigned patients with myocardial infarction and a hemoglobin level of less than 10 g per deciliter to a restrictive transfusion strategy (hemoglobin cutoff for transfusion, 7 or 8 g per deciliter) or a liberal transfusion strategy (hemoglobin cutoff, <10 g per deciliter). The primary outcome was a composite of myocardial infarction or death at 30 days. RESULTS: A total of 3504 patients were included in the primary analysis. The mean (±SD) number of red-cell units that were transfused was 0.7±1.6 in the restrictive-strategy group and 2.5±2.3 in the liberal-strategy group. The mean hemoglobin level was 1.3 to 1.6 g per deciliter lower in the restrictive-strategy group than in the liberal-strategy group on days 1 to 3 after randomization. A primary-outcome event occurred in 295 of 1749 patients (16.9%) in the restrictive-strategy group and in 255 of 1755 patients (14.5%) in the liberal-strategy group (risk ratio modeled with multiple imputation for incomplete follow-up, 1.15; 95% confidence interval [CI], 0.99 to 1.34; P = 0.07). Death occurred in 9.9% of the patients with the restrictive strategy and in 8.3% of the patients with the liberal strategy (risk ratio, 1.19; 95% CI, 0.96 to 1.47); myocardial infarction occurred in 8.5% and 7.2% of the patients, respectively (risk ratio, 1.19; 95% CI, 0.94 to 1.49). CONCLUSIONS: In patients with acute myocardial infarction and anemia, a liberal transfusion strategy did not significantly reduce the risk of recurrent myocardial infarction or death at 30 days. However, potential harms of a restrictive transfusion strategy cannot be excluded. (Funded by the National Heart, Lung, and Blood Institute and others; MINT ClinicalTrials.gov number, NCT02981407.).

E-Cigarette Use Among US Adults in the 2021 Behavioral Risk Factor Surveillance System Survey.

Importance: After the initial disruption from the COVID-19 pandemic, it is unclear how patterns of e-cigarette use in the US have changed. Objective: To examine recent patterns in current and daily e-cigarette use among US adults in 2021. Design, Setting, and Participants: This cross-sectional study used data from the 2021 Behavioral Risk Factor Surveillance System (BRFSS) database. The BRFSS is the largest national telephone-based survey of randomly sampled adults in the US. Adults aged 18 years or older, residing in 49 US states (all except Florida), the District of Columbia, and 3 US territories (Guam, Puerto Rico, and the US Virgin Islands), were included in the data set. Data analysis was performed in January 2023. Main Outcomes and Measures: The main outcome was age-adjusted prevalence of current and daily e-cigarette use overall and by participant characteristics, state, and territory. Descriptive statistical analysis was conducted, applying weights to account for population representation. Results: This study included 414 755 BRFSS participants with information on e-cigarette use. More than half of participants were women (51.3%). In terms of race and ethnicity, 0.9% of participants were American Indian or Alaska Native, 5.8% were Asian, 11.5% were Black, 17.3% were Hispanic, 0.2% were Native Hawaiian or Other Pacific Islander, 62.2% were White, 1.4% were of multiple races or ethnicities, and 0.6% were of other race or ethnicity. Individuals aged 18 to 24 years comprised 12.4% of the study population. The age-standardized prevalence of current e-cigarette use was 6.9% (95% CI, 6.7%-7.1%), with almost half of participants using e-cigarettes daily (3.2% [95% CI, 3.1%-3.4%]). Among individuals aged 18 to 24 years, there was a consistently higher prevalence of e-cigarette use, with more than 18.6% reporting current use and more than 9.0% reporting daily use. Overall, among individuals reporting current e-cigarette use, 42.2% (95% CI, 40.7%-43.7%) indicated former combustible cigarette use, 37.1% (95% CI, 35.6%-38.6%) indicated current combustible cigarette use, and 20.7% (95% CI, 19.7%-21.8%) indicated never using combustible cigarettes. Although relatively older adults (aged ≥25 years) who reported current e-cigarette use were more likely to report former or current combustible cigarette use, younger adults (aged 18-24 years) were more likely to report never using combustible cigarettes. Notably, the proportion of individuals who reported current e-cigarette use and never using combustible cigarettes was higher in the group aged 18 to 20 years (71.5% [95% CI, 66.8%-75.7%]) compared with those aged 21 to 24 years (53.0% [95% CI, 49.8%-56.1%]). Conclusion and Relevance: These findings suggest that e-cigarette use remained common during the COVID-19 pandemic, particularly among young adults aged 18 to 24 years (18.3% prevalence). Notably, 71.5% of individuals aged 18 to 20 years who reported current e-cigarette use had never used combustible cigarettes. These results underscore the rationale for the implementation and enforcement of public health policies tailored to young adults.

Investigating the association of traditional and non-traditional tobacco product use with subclinical and clinical cardiovascular disease: The Cross-Cohort Collaboration-Tobacco working group rationale, design, and methodology.

While the impact of combustible cigarette smoking on cardiovascular disease (CVD) is well-established, the longitudinal association of non-traditional tobacco products with subclinical and clinical CVD has not been fully explored due to: 1) limited data availability; and 2) the lack of well-phenotyped prospective cohorts. Therefore, there is the need for sufficiently powered well-phenotyped datasets to fully elucidate the CVD risks associated with non-cigarette tobacco products. The Cross-Cohort Collaboration (CCC)-Tobacco is a harmonized dataset of 23 prospective cohort studies predominantly in the US. A priori defined variables collected from each cohort included baseline characteristics, details of traditional and non-traditional tobacco product use, inflammatory markers, and outcomes including subclinical and clinical CVD. The definitions of the variables in each cohort were systematically evaluated by a team of two physician-scientists and a biostatistician. Herein, we describe the method of data acquisition and harmonization and the baseline sociodemographic and risk profile of participants in the combined CCC-Tobacco dataset. The total number of participants in the pooled cohort is 322782 (mean age: 59.7 ± 11.8 years) of which 76% are women. White individuals make up the majority (73.1%), although there is good representation of other race and ethnicity groups including African American (15.6%) and Hispanic/Latino individuals (6.4%). The prevalence of participants who never smoked, formerly smoked, and currently smoke combustible cigarettes is 50%, 36%, and 14%, respectively. The prevalence of current and former cigar, pipe, and smokeless tobacco is 7.3%, 6.4%, and 8.6%, respectively. E-cigarette use was measured only in follow-up visits of select studies, totaling 1704 former and current users. CCC-Tobacco is a large, pooled cohort dataset that is uniquely designed with increased power to expand knowledge regarding the association of traditional and non-traditional tobacco use with subclinical and clinical CVD, with extension to understudied groups including women and individuals from underrepresented racial-ethnic groups.

Comprehensive review of the national surveys that assess E-cigarette use domains among youth and adults in the United States.

Surveillance of e-cigarette use among different population groups is important for the timely implementation and evaluation of tobacco regulatory policies. In this review, we identified 13 nationally representative, repeatedly conducted epidemiologic surveys that assess e-cigarette use among U.S. youth and/or adults and have been instrumental in e-cigarette surveillance. These surveys included National Youth Tobacco Survey, Youth Risk Behavior Surveillance System, Monitoring the Future Survey, International Tobacco Control Policy Evaluation Project (ITC) Youth Tobacco and Vaping Survey, Behavioral Risk Factor Surveillance System, National Health Interview Survey, Tobacco Use Supplement of the Current Population Survey, Health Information National Trends Survey, Tobacco Products and Risk Perception Surveys, ITC Four Country Smoking and Vaping Survey, National Health and Nutrition Examination Survey, National Survey on Drug Use and Health, and Population Assessment of Tobacco and Health. These surveys vary in scope and detail, with their unique strengths and the regulatory questions that can be answered using each survey data. We also highlighted the gaps in these surveys and made recommendations for improvement.

Psychosocial stressors and current e-cigarette use in the youth risk behavior survey.

BACKGROUND: This study explores the association between psychosocial stressors and current e-cigarette use among adolescents in the United States. METHODS: We used data from 12,767 participants in the 2019 National Youth Risk Behavioral Survey to examine the association between psychosocial stressors (bullying, sexual assault, safety-related absence from school, depressive symptoms, suicidal ideation, physical altercation, and weapon threats) and past-30-day e-cigarette use using multivariable-adjusted logistic regression models. We examined the association for each stressor and then as a burden score (0-7). To compare the strength of the association between stressors and current e-cigarette use to current combustible cigarette use, we additionally examined the association between each stressor and current combustible cigarette use. RESULTS: Approximately 32.7% reported current e-cigarette use. The weighted prevalence of current e-cigarette use was higher among individuals who experienced stressors than those who did not. For example, bullying (43.9% vs. 29.0%). Similar prevalence patterns were seen among other stressors. Individuals who experienced stressors had significantly higher adjusted odds of current e-cigarette use than those who did not (OR [Odds Ratio] range: 1.47-1.75). Similarly, individuals with higher burden scores had a higher prevalence (zero [20.5%], one [32.8%], two [41.4%], three [49.6%], four to seven [60.9%]) and higher odds of current e-cigarette use (OR range: 1.43-2.73) than those with a score of zero. The strength of the association between the stressors and e-cigarette use was similar to that between the stressors and combustible cigarette use. CONCLUSION: The study demonstrates a significant association between psychosocial stressors and adolescent e-cigarette use, highlighting the potential importance of interventions, such as targeted school-based programs that address stressors and promote stress management, as possible means of reducing adolescent e-cigarette use. Future research directions include exploring underlying mechanisms linking stressors to e-cigarette use and evaluating the effectiveness of interventions addressing stressors in reducing adolescent e-cigarette use.

Patterns of tobacco product use and substance misuse among adolescents in the United States.

Among adolescents, sole use is the most common pattern of e-cigarette use. However, concurrent use of e-cigarettes with other tobacco products is not uncommon and may be associated with high-risk behaviors. We used data from 12,767 participants in the 2019 Youth Risk Behavior Survey to examine the patterns of tobacco product use among youth in the US. First, we examined the prevalence of e-cigarette-specific patterns of tobacco use (nonuse[no tobacco product use], sole use[sole e-cigarette use], dual-use[e-cigarette and one other tobacco product], and poly use[e-cigarette and two or more other tobacco products]). Then, using multivariable Poisson regression, we assessed how the tobacco use patterns were associated with the misuse of nine substances of abuse (alcohol, marijuana, cocaine, ecstasy, hallucinogens, heroin, inhalants, injectables, and methamphetamines). 62.9% of youth reported nonuse of any tobacco product. The weighted prevalence of sole e-cigarette use, dual use, and poly use was 23.2%, 4.2%, and 3.3%, respectively. Across all the substances explored, the prevalence was highest among poly users, followed by dual users, sole users, and non-users. Compared to non-users, sole, dual, and poly users had 7.8(95 %CI:6.1-10.0), 14.3(95 %CI:10.8-18.8), and 19.7(95 %CI:15.0-25.9) times higher adjusted prevalence of reporting past-30-day binge drinking, after adjusting for age, sex, race/ethnicity, sexual orientation, and depressive symptoms. This pattern was seen across all the different substances explored. These findings highlight the high prevalence of substance misuse among youth who use tobacco products and the need to educate and counsel on substances of abuse among this population, particularly among poly-tobacco users.

Association of Electronic Cigarette Exposure on Cardiovascular Health: A Systematic Review and Meta-Analysis.

Despite the growing use of electronic cigarettes (EC) in the Unites States, particularly among young people, and their perceived safety, current evidence suggests that EC usage may cause adverse clinical cardiovascular effects. Therefore, we aim to pool all studies evaluating the association of EC exposure with cardiovascular health. Medline, Cochrane CENTRAL, and Scopus were searched for studies from January 1, 2006 until December 31, 2022. Randomized and observational studies reporting cardiovascular outcomes, hemodynamic parameters, and biomarkers of platelet physiology, before and after acute or chronic EC exposure were pooled using a random-effects model. Overall, 27 studies (n = 863) were included. Heart rate increased significantly after acute EC exposure (weighted mean difference [WMD]: 0.76 bpm; 95% confidence interval [CI], 0.48, 1.03; P < 0.00001; I2 = 92%). Significant increases in systolic blood pressure (WMD: 0.28 mmHg; 95% CI, 0.06, 0.51; P = 0.01; I2 = 94%), diastolic blood pressure (WMD: 0.38 mmHg; 95% CI, 0.16, 0.60; P = 0.0006; I2 = 90%), and PWV (WMD: 0.38; 95% CI, 0.13, 0.63; P = 0.003; I2 = 100%) were also observed. Augmentation index increased significantly (SMD: 0.39; 95% CI, 0.11, 0.67; P = 0.007; I2 = 90%), whereas reduction in flow-mediated dilation (WMD: -1.48; 95% CI, -2.49, -0.47; P = 0.004; I2 = 45%) was observed. Moreover, significant rise in both soluble P-selectin (WMD: 4.73; 95% CI, 0.80, 8.66; P = 0.02; I2 = 98%) and CD40L (WMD: 1.14; 95% CI, 0.41, 1.87; P = 0.002; I2 = 79%) was observed. Our results demonstrate that smoking EC is associated with a significant increase in cardiovascular hemodynamic measures and biomarkers. Our findings can aid policymakers in making informed decisions regarding the regulation of EC to ensure public safety.

Pod-based e-cigarette use among US college-aged adults: A survey on the perception of health effects, sociodemographic correlates, and interplay with other tobacco products.

INTRODUCTION: E-cigarette use among youth and young adults remains of public health concern. Pod-based e-cigarettes, including JUUL, significantly changed the e-cigarette landscape in the US. Using an online survey, we explored the socio-behavioral correlates, predisposing factors, and addictive behaviors, among young adult pod-mod users within a University in Maryland, USA. METHODS: In total, 112 eligible college students aged 18-24 years, recruited from a University in Maryland, who reported using pod-mods were included in this study. Participants were categorized into current/non-current users based on past-30-day use. Descriptive statistics were used to analyze participants' responses. RESULTS: The mean age of the survey participants was 20.5 ± 1.2 years, 56.3% were female, 48.2% White, and 40.2% reported past-30-day (current) use of pod-mods. The mean age of first experimentation with pod-mods was 17.8 ± 1.4 years, while the mean age of regular use was 18.5 ± 1.4 years, with the majority (67.9%) citing social influence as the reason for initiation. Of the current users, 62.2% owned their own devices, and 82.2% predominantly used JUUL and menthol flavor (37.8%). A significant proportion of current users (73.3%) reported buying pods in person, 45.5% of whom were aged <21 years. Among all participants, 67% had had a past serious quit attempt. Among them, 89.3% neither used nicotine replacement therapy nor prescription medications. Finally, current use (adjusted odds ratio, AOR=4.52; 95% CI: 1.76-11.64), JUUL use (AOR=2.56; 95% CI: 1.08-6.03), and menthol flavor (AOR=6.52; 95% CI: 1.38-30.89) were associated with reduced nicotine autonomy, a measure of addiction. CONCLUSIONS: Our findings provide specific data to inform the development of public health interventions targeted at college youth, including the need for more robust cessation support for pod-mod users.

Risk factor associations with individual myocardial infarction subtypes and acute non-ischemic myocardial injury in the Multi-Ethnic Study of Atherosclerosis (MESA): Design and rationale.

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 baseline 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.

Blood Levels of Angiotensinogen and Hypertension in the Multi-Ethnic Study of Atherosclerosis (MESA).

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 hypertension 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.

Rationale and design for the myocardial ischemia and transfusion (MINT) randomized clinical trial.

BACKGROUND: Accumulating evidence from clinical trials suggests that a lower (restrictive) hemoglobin threshold (<8 g/dL) for red blood cell (RBC) transfusion, compared with a higher (liberal) threshold (≥10 g/dL) is safe. However, in anemic patients with acute myocardial infarction (MI), maintaining a higher hemoglobin level may increase oxygen delivery to vulnerable myocardium resulting in improved clinical outcomes. Conversely, RBC transfusion may result in increased blood viscosity, vascular inflammation, and reduction in available nitric oxide resulting in worse clinical outcomes. We hypothesize that a liberal transfusion strategy would improve clinical outcomes as compared to a more restrictive strategy. METHODS: We will enroll 3500 patients with acute MI (type 1, 2, 4b or 4c) as defined by the Third Universal Definition of MI and a hemoglobin <10 g/dL at 144 centers in the United States, Canada, France, Brazil, New Zealand, and Australia. We randomly assign trial participants to a liberal or restrictive transfusion strategy. Participants assigned to the liberal strategy receive transfusion of RBCs sufficient to raise their hemoglobin to at least 10 g/dL. Participants assigned to the restrictive strategy are permitted to receive transfusion of RBCs if the hemoglobin falls below 8 g/dL or for persistent angina despite medical therapy. We will contact each participant at 30 days to assess clinical outcomes and at 180 days to ascertain vital status. The primary end point is a composite of all-cause death or recurrent MI through 30 days following randomization. Secondary end points include all-cause mortality at 30 days, recurrent adjudicated MI, and the composite outcome of all-cause mortality, nonfatal recurrent MI, ischemia driven unscheduled coronary revascularization (percutaneous coronary intervention or coronary artery bypass grafting), or readmission to the hospital for ischemic cardiac diagnosis within 30 days. The trial will assess multiple tertiary end points. CONCLUSIONS: The MINT trial will inform RBC transfusion practice in patients with acute MI.

E-cigarette use among high school students in the United States prior to the COVID-19 pandemic: Trends, correlates, and sources of acquisition.

Detailed description of the prevalence and sources of e-cigarettes among youth is needed to inform effective regulatory policies. We used the Youth Risk Behavior Surveillance System data (2015-2019) to assess trends in current (past-30-day-use) and frequent (≥10 days in past-30-days) e-cigarette use among United States high schoolers before the COVID-19 pandemic. First, we assessed trends overall and then stratified by participants' sociodemographic characteristics, use of other tobacco products, and experiences of psychosocial stress. We also evaluated past year quit attempts and the changing sources of e-cigarettes. Our sample size was 41,021 (15,356-2015; 12,873-2017; 12,792-2019). The prevalence of current e-cigarette use increased from 24.0% (95%CI:21.9%-26.3%) in 2015 to 32.7% (30.4%-35.1%) in 2019. The proportion of current users who reported frequent use also increased significantly from 22.6% (20.4%-24.8%) to 45.4% (42.7%-48.2%). Thus, an increasing proportion of US high school students who use e-cigarettes reported frequent use, indicating greater nicotine dependence. The increase in current and frequent e-cigarette use was more pronounced in youth who reported other substance use and psychosocial stressors such as bullying. Between 2017 and 2019, there was a decline in the proportion of youth who bought e-cigarettes online (6.9% to 3.2%) or from convenience stores (22.0% to 16.6%). Conversely, there was an increase in the proportion who borrowed (34.5% to 40.1%) or purchased e-cigarettes through other people (10.7% to 18.0%), indicating that most youth are evading age-related restrictions by obtaining e-cigarettes from other people. Finally, a considerable proportion of youth tobacco users are making quit attempts; 47.6% (45.1%-50.1%) in 2019.

Angiotensinogen: More Than its Downstream Products: Evidence From Population Studies and Novel Therapeutics.

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.

Smoking is associated with increased risk of cardiovascular events, disease severity, and mortality among patients hospitalized for SARS-CoV-2 infections.

The clinical sequalae of SARS-CoV-2 infection are in part dependent upon age and pre-existing health conditions. Although the use of tobacco products decreases cardiorespiratory fitness while increasing susceptibility to microbial infections, limited information is available on how smoking affects COVID-19 severity. Therefore, we examined whether smokers hospitalized for COVID-19 are at a greater risk for developing severe complications than non-smokers. Data were from all hospitalized adults with SARS-CoV-2 infection from the American Heart Association's Get-With-The-Guidelines COVID-19 Registry, from January 2020 to March 2021, which is a hospital-based voluntary national registry initiated in 2019 with 122 participating hospitals across the United States. Patients who reported smoking at the time of admission were classified as smokers. Severe outcome was defined as either death or the use of mechanical ventilation. Of the 31,545 patients in the cohort, 6,717 patients were 1:2 propensity matched (for age, sex, race, medical history, medications, and time-frame of hospital admission) and classified as current smokers or non-smokers according to admission data. In multivariable analyses, after adjusting for sociodemographic characteristics, medical history, medication use, and the time of hospital admission, patients self-identified as current smokers had higher adjusted odds of death (adjusted odds ratio [aOR], 1.41; 95% CI, 1.21-1.64), the use of mechanical ventilation (aOR 1.15; 95% CI 1.01-1.32), and increased risk of major adverse cardiovascular events (aOR, 1.27; 95% CI 1.05-1.52). Independent of sociodemographic characteristics and medical history, smoking was associated with a higher risk of severe COVID-19, including death.

Assessment of Patterns in e-Cigarette Use Among Adults in the US, 2017-2020.

Importance: Updated data on the patterns of e-cigarette use among adults in the US are needed. Objective: To examine recent patterns in current and daily e-cigarette use among US adults. Design, Setting, and Participants: This repeated cross-sectional study used data from the 2017, 2018, and 2020 Behavioral Risk Factor Surveillance System, a nationally representative state-based survey of noninstitutionalized US adults. A total of 994 307 adults 18 years and older who were living in states and territories that provided data on e-cigarette use in 2017 (53 states and territories), 2018 (36 states and Guam), and 2020 (42 states and Guam) were included. Main Outcomes and Measures: The weighted prevalence of current (past 30 days) and daily e-cigarette use was estimated for each year, and changes in prevalence from 2017 to 2020 were assessed, first overall and then stratified by participant characteristics, including state or territory of residence. Results: Among 994 307 adults from states with data on e-cigarette use, 429 370 individuals (weighted 51.3% female) were participants in the 2017 survey, 280 184 (weighted 52.1% female) were participants in the 2018 survey, and 284 753 (weighted 52.1% female) were participants in the 2020 survey. The weighted proportions of young adults aged 18 to 24 years were 12.6% in 2017, 11.8% in 2018, and 11.9% in 2020. Across all 3 years, 17 035 participants (weighted, 1.0%) were American Indian or Alaska Native, 22 313 (weighted, 4.6%) were Asian, 75 780 (weighted, 12.2%) were Black, 72 190 (weighted, 15.1%) were Hispanic, 4817 (weighted, 0.2%) were Native Hawaiian, 757 140 (weighted, 65.1%) were White, 20 332 (weighted, 1.3%) were multiracial, and 6245 (weighted, 0.5%) were of other races and/or ethnicities. The prevalence of current e-cigarette use was 4.4% (95% CI, 4.3%-4.5%) in 2017, which increased to 5.5% (95% CI, 5.4%-5.7%) in 2018 and decreased slightly to 5.1% (95% CI, 4.9%-5.3%) in 2020. The recent decrease, though modest, was observed mainly among young adults aged 18 to 20 years (from 18.9% [95% CI, 17.2%-20.7%] to 15.6% [95% CI, 14.1%-17.1%]; P = .004). However, the prevalence of daily e-cigarette use increased consistently from 1.5% (95% CI, 1.4%-1.6%) in 2017 to 2.1% (95% CI, 2.0%-2.2%) in 2018 and 2.3% (95% CI, 2.2%-2.4%) in 2020. Among young adults aged 21 to 24 years, there was a slight, albeit insignificant, increase in the prevalence of current e-cigarette use (from 13.5% [95% CI, 12.3%-14.7%] to 14.5% [95% CI, 13.2%-15.9%]; P = .28) but a significant increase in the prevalence of daily e-cigarette use (from 4.4% [95% CI, 3.8%-5.1%] to 6.6% [95% CI, 5.6%-7.6%]; P < .001) between 2018 and 2020. State-level patterns in the prevalence of current e-cigarette use were heterogeneous, with states like Massachusetts (from 5.6% [95% CI, 4.8%-6.5%] to 4.1% [95% CI, 3.1%-5.3%]; P = .03) and New York (from 5.4% [95% CI, 4.9%-5.9%] to 4.1% [95% CI, 3.5%-4.7%]; P = .001) recording significant decreases between 2018 and 2020. In contrast, Guam (from 5.9% [95% CI, 4.5%-7.9%] to 11.4% [95% CI, 8.7%-14.8%]; P = .002) and Utah (from 6.1% [95% CI, 5.5%-6.7%] to 7.2% [95% CI, 6.5%-8.0%]; P = .02) recorded significant increases in current e-cigarette use over the same period. Conclusions and Relevance: In this study, a slight decrease in the prevalence of current e-cigarette use was found between 2018 and 2020; this decrease was mainly observed among young adults aged 18 to 20 years. In contrast, daily e-cigarette use consistently increased, particularly among young adults aged 21 to 24 years. This increase in daily use suggests greater nicotine dependence among those who use e-cigarettes, warranting continued surveillance.

In-vivo platelet activation and aggregation during and after acute atherothrombotic myocardial infarction in patients with and without Type-2 diabetes mellitus treated with ticagrelor.

INTRODUCTION: Patients with type-2 diabetes are twice as likely to suffer from acute myocardial infarction (AMI) and have a higher incidence of recurrent events than their non-diabetic counterparts. Ticagrelor is a platelet inhibitor known to reduce major adverse cardiovascular events (MACE) in AMI patients. This study measures the level and change in platelet activation and aggregation at the time of and following an AMI in patients with and without diabetes treated with ticagrelor. MATERIALS/METHODS: P2Y12 receptor inhibitor naïve patients presenting with AMI were prospectively enrolled. Blood collection occurred before coronary angiography (baseline: T0), 2, 4, 24, 48 h after baseline, and at a three-month follow-up. Ticagrelor was administered within five minutes of T0. We assessed platelet activation via measurements of surface P-selectin and platelet activated glycoprotein IIb/IIIa-1 (PAC-1) and assessed platelet aggregation via monocyte, lymphocyte, and granulocyte aggregates. We hypothesize that platelet activation and aggregation will be proportionally impacted to the same degree by ticagrelor, regardless of diabetes status. RESULTS: Ninety-seven patients were prospectively enrolled (diabetes, N = 33; no diabetes, N = 64). No difference was observed in the expression of P-selectin and PAC-1 at any given point between diabetes and non-diabetes groups (p > 0.05). No difference was observed in the percentage of platelet bound to leukocytes at any measured timepoint between patients with and without diabetes (p > 0.05). Platelet leukocyte aggregation was suppressed during the acute phase compared to quiescence equally among both groups. DISCUSSION: Ticagrelor demonstrated similar in-vivo effects on platelet activation and aggregation regardless of diabetes status in patients presenting with AMI.

The Interplay of Race/Ethnicity and Obesity on the Incidence of Venous Thromboembolism.

INTRODUCTION: Factors predisposing asymptomatic individuals within the community to venous thromboembolism are not fully understood. This study characterizes the incidence and determinants of venous thromboembolism among the Multiethnic Study of Atherosclerosis cohort with a focus on race/ethnicity and obesity. METHODS: This study (analyzed in 2020-2021) used the Multiethnic Study of Atherosclerosis cohort (2000-2017), which included participants with diverse ethnic/racial backgrounds aged 45-84 years without cardiovascular disease at baseline. The primary endpoint was time to diagnosis of venous thromboembolism defined using International Classification of Diseases codes (415, 451, 453, 126, 180, and 182). Multivariable-adjusted hazard ratios of the predictors of venous thromboembolism were calculated with a focus on the interaction between obesity and race/ethnicity categories. RESULTS: Over a median follow-up period of 14 years, 233 individuals developed venous thromboembolism. Incidence rates (per 1,000 person-years) varied across racial/ethnic groups with the highest incidence among Black (4.02) followed by White (2.98), Hispanic (2.08), and Chinese (0.79) participants. There was a stepwise increase in the incidence rate of venous thromboembolism with increasing BMI regardless of race/ethnicity: normal (1.95), overweight (2.52), obese (3.63), and morbidly obese (4.55). The association between BMI and venous thromboembolism was strongest among non-White women with the highest incidence rate for obese (4.8) compared with non-obese (1.6). The interaction among obesity, gender, and race was statistically significant (p=0.01) in non-White obese women. Risk of venous thromboembolism increased with age for all race/ethnicities. CONCLUSIONS: This study finds that obesity may confer an increased risk for venous thromboembolism among non-White women compared with other groups-White men, White women, and non-White men.