Oxidative Stress and Cardiovascular Risk Factors: The Coronary Artery Risk Development in Young Adults (CARDIA) Study.

Introduction-Oxidative stress is linked to cardiovascular diseases (CVD) and is suggested to vary by sex. However, few population-level studies have explored these associations and the majority comprise populations with advanced CVD. We assessed urinary isoprostane concentrations, a standard measure of oxidative stress, in a relatively young and healthy cohort, hypothesizing that higher oxidative stress is associated with an adverse cardiometabolic profile and female sex. Methods-Oxidative stress was measured in 475 women and 266 men, aged 48-55 years, from the Coronary Artery Risk Development in Young Adults (CARDIA) study using urinary 8-isoprostane (IsoP) and 2,3-dinor-8-isoprostane (IsoP-M). Multivariable-adjusted regression was used to evaluate cross-sectional associations. As secondary analysis, previously measured plasma F2-isoprostanes (plasma IsoP) from another CARDIA subset was similarly analyzed. Results-Mean (SD) ages for men and women were 52.1(2.3) and 52.2(2.2) years, respectively (p = 0.46), and 39% of the participants self-identified as Black (vs. White). Before adjustments, female sex was associated with higher median urinary IsoP (880 vs. 704 ng/g creatinine in men; p < 0.01) and IsoP m (1675 vs. 1284 ng/g creatinine in men; p < 0.01). Higher body mass index (BMI), high-density cholesterol (HDL-C), and triglycerides, current smoking, and less physical activity were associated with higher oxidative stress. Diabetes was not associated with urinary IsoP but was associated with lower IsoP m and plasma IsoP. Higher serum creatinine showed diverging associations with higher plasma and lower urinary isoprostane concentrations. Conclusions-Different isoprostane entities exhibit varying association patterns with CVD risk factors, and therefore are complementary, rather than interchangeable, in assessment of oxidative stress. Still, consistently higher isoprostanes among women, smokers, less active persons, and those with higher BMI and plasma triglycerides could reflect higher oxidative stress among these groups. While urinary isoprostanes are indexed to urinary creatinine due to variations in concentration, caution should be exercised when comparing groups with differing serum creatinine.

Association of HIV infection with clinical features and outcomes of patients with aortic aneurysms.

Data on the characteristics and outcomes of hospitalized patients with aortic aneurysms (AA) and HIV remain scarce. This is a cohort study of hospitalized adult patients with a diagnosis of AA from 2013 to 2019 using the US National Inpatient Readmission Database. Patients with a diagnosis of HIV were identified. Our outcomes included trends in hospitalizations and comparison of clinical characteristics, complications, and mortality in patients with AA and HIV compared to those without HIV. Among 1,905,837 hospitalized patients with AA, 4416 (0.23%) were living with HIV. There was an overall age-adjusted increase in the rate of HIV among patients hospitalized with AA over the years (14-29 per 10,000 person-years; age-adjusted p-trend < 0.001). Patients with AA and HIV were younger than those without HIV (median age: 60 vs 76 years, p < 0.001) and were less likely to have a history of smoking, hypertension, dyslipidemia, diabetes mellitus, and obesity. Thoracic aortic aneurysms were more prevalent in those with HIV (37.5% vs 26.7%, p < 0.001). On multivariable logistic regression, HIV was not associated with increased risk of aortic rupture (OR: 0.79; 95% CI: 0.61-1.01, p = 0.06), acute aortic dissection (OR: 0.73; 95% CI: 0.51-1.06, p = 0.3), readmissions (OR: 1.04; 95% CI: 0.95-1.13, p = 0.4), or aortic repair (OR: 0.89; 95% CI: 0.79-1.00, p = 0.05). Hospitalized patients with AA and HIV had a lower crude mortality rate compared to those without HIV (OR: 0.75 (0.63-0.91), p = 0.003). Hospitalized patients with AA and HIV likely constitute a distinct group of patients with AA; they are younger, have fewer traditional cardiovascular risk factors, and a higher rate of thoracic aorta involvement. Differences in clinical features may account for the lower mortality rate observed in patients with AA and HIV compared to those without HIV.

Coronary Artery Calcium Score to Refine the Use of PCSK9i in Asymptomatic Individuals: A Multicohort Study.

Background The value of coronary artery calcium (CAC) in the allocation of PCSK9i (proprotein convertase subtilisin/kexin type 9 inhibitors) among individuals without clinically evident atherosclerotic cardiovascular disease (ASCVD) is unknown for indications that do not require confirmed familial hypercholesterolemia. We aimed to assess the ability of CAC to stratify ASCVD risk under 3 non-familial hypercholesterolemia PCSK9i allocation paradigms. Methods and Results We included participants without clinically evident ASCVD from MESA (Multi-Ethnic Study of Atherosclerosis), CARDIA (Coronary Artery Risk Development in Young Adults) study, DHS (Dallas Heart Study), and HNR (Heinz Nixdorf Recall) study. Three PCSK9i eligibility scenarios were defined: a broad scenario informed only by high low-density lipoprotein cholesterol levels (N=567), a restrictive one combining higher low-density lipoprotein cholesterol levels and presence of ≥2 additional risk factors (N=127), and a high-risk scenario where individuals with subclinical organ damage or high estimated risk would be treated to achieve low-density lipoprotein cholesterol <55 mg/dL (N=471). The high-risk scenario had the highest ASCVD event rates (27.8% at 10 years). CAC=0 was observed in 35% participants in the broad scenario, 25% in the restrictive scenario, and 16% in the high-risk scenario. In all, CAC=0 was associated with the lowest incident ASCVD rates at 5 and 10 years, and CAC burden was independently associated with ASCVD events adjusting for traditional risk factors. Conclusions CAC may be used to refine the allocation of PCSK9i, potentially leading to a more conservative use if CAC=0. The value of CAC testing is greater in scenarios that use low-density lipoprotein cholesterol levels and/or traditional risk factors to define PCSK9i eligibility (CAC=0 present in 1 of 3-4 patients), whereas its prevalence is lower when allocation is informed by presence of noncoronary subclinical organ damage.

Oxidative Stress and Menopausal Status: The Coronary Artery Risk Development in Young Adults Cohort Study.

Background: Low endogenous estrogen concentrations after menopause may contribute to higher oxidative stress and greater cardiovascular disease (CVD) risk. However, differences in oxidative stress between similarly aged premenopausal and postmenopausal women are not well-characterized on a population level. We hypothesized that urinary isoprostane concentrations, a standard measure of systemic oxidative stress, are higher in women who have undergone menopause compared to premenopausal women. Methods and Results: We examined differences in urinary 8-isoprostane (iPF2α-III) and 2,3-dinor-8-isoprostane (iPF2α-III-M) indexed to urinary creatinine between 279 postmenopausal and 196 premenopausal women in the Coronary Artery Risk Development in Young Adults (CARDIA) study, using linear regression with progressive adjustment for sociodemographic factors and traditional CVD risk factors. Unadjusted iPF2α-III-M concentrations were higher among postmenopausal compared to premenopausal women (Median [25th, 75th percentile]: 1762 [1178, 2974] vs. 1535 [1067, 2462] ng/g creatinine; p = 0.01). Menopause was associated with 25.5% higher iPF2α-III-M (95% confidence interval [6.5-47.9]) adjusted for age, race, college education, and field center. Further adjustments for tobacco use (21.2% [2.9-42.6]) and then CVD risk factors (18.8% [0.1-39.6]) led to additional partial attenuation. Menopause was associated with higher iPF2α-III in Black but not White women. Conclusions: We conclude that postmenopausal women had higher oxidative stress, which may contribute to greater CVD risk. ClinicalTrials.gov Identifier: NCT00005130.

Assessment of left ventricle myocardial deformation in a hemorrhagic shock swine model by two-dimensional speckle tracking echocardiography.

BACKGROUND: Trauma-induced secondary cardiac injury has been associated with significant adverse cardiovascular events. Speckle tracking echocardiography is a novel technology that allows an accurate and reproducible cardiac structure and function assessment. We evaluated the left ventricle (LV) myocardial deformation by speckle tracking echocardiography in a hemorrhagic shock (HS) swine model. METHODS: Seven healthy male Landrace pigs were included in this study. Severe HS was reached through three sequentially blood withdraws of 20% of estimated blood volume, and it was maintained for 60 minutes. Volume resuscitation was performed using all precollected blood volume. A 1.8- to 4.2-MHz phased-array transducer was used to acquire the two-dimensional echocardiography images. Strain measurements were obtained semiautomatically by wall motion tracking software. Results are presented as medians and interquartile ranges and compared using Wilcoxon rank-sum test. A p value of <0.05 was considered statistically significant. RESULTS: The median weight was 32 (26.1-33) kg, and the median total blood volume withdrawn was 1,100 (1,080-1,190) mL. During the severe HS period, the median arterial systemic pressure was 39 (36-46) mm Hg, and the cardiac index was 1.7 (1.6-2.0) L/min/m 2 . There was statistically significant absolute decrease in the global longitudinal strain 2 hours postresuscitation comparing with the basal measurements (-9.6% [-10.7 to -8.0%] vs. -7.9% [-8.1 to -7.4%], p = 0.03). There were no statistically significant differences between the basal and 2 hours postresuscitation assessments in the invasive/noninvasive hemodynamic, other two-dimensional echocardiogram (LV ejection fraction, 49.2% [44-54.3%] vs. 53.2% [51.5-55%]; p = 0.09), and circumferential strain (-10.6% [-14.4 to -9.0%] vs. -8.5% [-8.6 to -5.2%], p = 0.06) parameters. CONCLUSION: In this experimental swine model of controlled HS, LV global longitudinal strain analysis accurately characterizes the timing and magnitude of subclinical cardiac dysfunction associated with trauma-induced secondary cardiac injury.

Association of HIV Serostatus and Inflammation With Ascending Aortic Size.

Background The prevalence and extent of subclinical large vessel vasculopathy is not well defined among people living with HIV. We aimed to evaluate associations between aortic root and ascending aortic sizes measured by 2-dimensional transthoracic echocardiography and HIV serostatus, and to identify risk factors for larger aortic sizes among men with HIV, including levels of circulating inflammatory markers. Methods and Results Using clinical and echocardiographic data from the MACS (Multicenter AIDS Cohort Study), adjusted multivariable linear and logistic regression was performed. Four segments of the proximal aorta were measured: aortic annulus, aortic root at the sinuses of Valsalva, sinotubular junction, and ascending aorta. HIV infection was associated with significantly larger aortic root (0.03 cm [95% CI, 0.002-0.06 cm]) and ascending aorta (0.04 cm [95% CI, 0.01-0.06 cm]) diameters. Higher standardized nadir CD4 (cluster of differentiation 4) T-cell count was significantly associated with smaller aortic root (-0.03 cm [95% CI, -0.05 to -0.01 cm]), sinotubular junction (-0.03 cm [95% CI, -0.05 to -0.01 cm]), and ascending aorta (-0.03 cm [95% CI, -0.05 to -0.004 cm]) diameters. Higher levels of standardized TNF-α (tumor necrosis factor-α) were associated with larger diameters of the aortic annulus (0.02 cm [95% CI, 0.003-0.04 cm]) and sinotubular junction (0.02 cm [95% CI, 0.002-0.04 cm]). There were no other cardiovascular or HIV disease severity-related risk factors associated with the aortic dimensions. Conclusions HIV infection is an independent risk factor for greater ascending aortic sizes. Lower nadir CD4 T-cell count and higher TNF-α levels are associated with larger aortic sizes in men with HIV. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT00046280.

CAC for Risk Stratification Among Individuals With Hypertriglyceridemia Free of Clinical Atherosclerotic Cardiovascular Disease.

OBJECTIVES: In this study, we sought to evaluate whether the coronary artery calcium (CAC) score can enhance current paradigms for risk stratification among individuals with hypertriglyceridemia in primary prevention. The eligibility criteria for icosapent ethyl (IPE) were used as case example. BACKGROUND: Recent trials of atherosclerotic cardiovascular disease (ASCVD) risk-reduction therapies for individuals with hypertriglyceridemia without clinical ASCVD restricted enrollment to participants with diabetes or various other risk factors. These criteria were mirrored in the Food and Drug Administration product label for IPE. METHODS: We pooled 2,345 participants with triglycerides 150 to <500 mg/dL (or >178-<500 mg/dL if not on a statin) and without clinical ASCVD from MESA, CARDIA, the Dallas Heart Study, and the Heinz Nixdorf Recall study. We evaluated the incidence of ASCVD events overall, by IPE eligibility (as defined in the product label), and further stratified by CAC scores (0, >0-100, >100). The number needed to treat for 5 years (NNT5) to prevent 1 event was estimated among IPE-eligible participants, assuming a 21.8% relative risk reduction with IPE. In exploratory analyses, the NNT5 was also estimated among noneligible participants. RESULTS: There was marked heterogeneity in CAC burden overall (45% CAC 0; 24% CAC >100) and across IPE eligibility strata. Overall, 17% of participants were eligible for IPE and 11.9% had ASCVD events within 5 years. Among participants eligible for IPE, 38% had CAC >100, and their event rates were markedly higher (15.9% vs 7.2%) and the NNT5 2.2-fold lower (29 vs 64) than those of the 25% eligible participants with CAC 0. Among the 83% participants not eligible for IPE, 20% had CAC >100, and their 5-year incidence of ASCVD (13.9%) was higher than the overall incidence among IPE-eligible participants. CONCLUSIONS: CAC can improve current risk stratification and therapy allocation paradigms among individuals with hypertriglyceridemia without clinical ASCVD. Future trials of risk-reduction therapies in hypertriglyceridemia could use CAC >100 to enroll a high-risk study sample, with implications for a larger target population.

Associations between menopause, cardiac remodeling, and diastolic function: the CARDIA study.

OBJECTIVES: Heart failure with preserved ejection fraction (HFpEF) affects more women than men. Menopause may influence HFpEF development in women. We assessed cross-sectional and longitudinal associations between menopause and echocardiographic measures of left ventricular (LV) function and cardiac remodeling. METHODS: We studied 1,723 women with available echo data from at least two of: year 5 (Y5) (1990-1991), Y25 (2010-2011), or Y30 (2015-2016) in the Coronary Artery Risk Development in Young Adults study. Cardiac structure and function were measured using 2D and Doppler echocardiography. Cross-sectional associations between menopausal status and repeated echo measures at Y25 and Y30 were analyzed using linear mixed models. Two-segmented models were used to compare longitudinal changes in echocardiographic measures in the premenopausal period to changes in the postmenopausal period. RESULTS: Mean ±â€ŠSD age (years) at enrollment was 27 ±â€Š3 in those with menopause by Y25, 25 ±â€Š3 in those with menopause between Y25 and Y30, and 21 ±â€Š3 in those premenopausal at Y30. There were no significant differences in race, body mass index, systolic blood pressure, or diabetes between the groups. Postmenopausal women had higher early diastolic mitral inflow (E) to annular (e') velocity ratio than premenopausal after adjusting for demographics and risk factors (P < 0.05). Menopause was associated with relative increases in the rates of change in LV mass and left atrial volume, even after adjustment. Change in E/e' ratio was similar before and after menopause. CONCLUSIONS: Menopause is associated cross-sectionally with worse diastolic function and longitudinally with adverse LV and left atrial remodeling. This may contribute to the increased HFpEF risk in postmenopausal women.

Video Summary:http://links.lww.com/MENO/A787 .

Associations Between HIV Serostatus and Cardiac Structure and Function Evaluated by 2-Dimensional Echocardiography in the Multicenter AIDS Cohort Study.

Background We aimed to investigate whether there are differences in cardiac structure and systolic and diastolic function evaluated by 2-dimensional echocardiography among men living with versus without HIV in the era of combination antiretroviral therapy. Methods and Results We performed a cross-sectional analysis of 1195 men from MACS (Multicenter AIDS Cohort Study) who completed a transthoracic echocardiogram examination between 2017 and 2019. Associations between HIV serostatus and echocardiographic indices were assessed by multivariable regression analyses, adjusting for demographics and cardiovascular risk factors. Among men who are HIV+, associations between HIV disease severity markers and echocardiographic parameters were also investigated. Average age was 57.1±11.9 years; 29% of the participants were Black, and 55% were HIV+. Most men who were HIV+ (77%) were virally suppressed; 92% received combination antiretroviral therapy. Prevalent left ventricular (LV) systolic dysfunction (ejection fraction <50%) was low and HIV serostatus was not associated with left ventricular ejection fraction. Multivariable adjustment models showed that men who were HIV+ versus those who were HIV- had greater LV mass index and larger left atrial diameter and right ventricular (RV) end-diastolic area; lower RV function; and higher prevalence of diastolic dysfunction. Higher current CD4+ T cell count ≥400 cell/mm3 versus <400 was associated with smaller LV diastolic volume and RV area. Virally suppressed men who were HIV+ versus those who were HIV- had higher indexed LV mass and left atrial areas and greater diastolic dysfunction. Conclusions HIV seropositivity was independently associated with greater LV mass index, left atrial and RV sizes, lower RV function and diastolic abnormalities, but not left ventricular ejection fraction, which may herald a future predisposition to heart failure with preserved ejection fraction among men living with HIV.

The Investigation of Left Atrial Structure and Stroke Etiology: The I-LASER Study.

Background Left atrial (LA) function is important in stroke, but often poorly characterized. We evaluated the association of 2-dimensional speckle tracking echocardiography LA variables with stroke subtype (cardioembolic stroke [CS] or cryptogenic stroke versus other). The hypothesis is worse LA active function is associated with CS, but not cryptogenic strokes. Methods and Results In this prospective cohort (2017-2019), left ventricular/LA structure and function were quantified by 2-dimensional and speckle tracking echocardiography in 151 patients with stroke. Strain/strain rate curves for the 3 components of the LA cycle, ie, (1) Reservoir (global longitudinal strain [Srmax]), (2) Conductive (early LA Sr [Sre]), and (3) Active (late LA strain [Sra]) were evaluated, masked to stroke subtype. Associations of cardiac features with stroke subtype were tested using multivariable logistic regressions. Odds of CS were increased in patients with a larger LA systolic diameter (odds ratio [OR], 2.96, 95% CI, 1.14-7.69) but reduced in patients with a higher Srmax (better reservoir) (OR, 0.80, 95% CI, 0.67-0.97). Lower Sra (worse function) was associated with an increased odds of CS (OR, 1.72, 95% CI, 1.07-2.76) but not independent of atrial fibrillation. Higher active LA emptying fraction (better active phase) was associated with reduced odds of CS (OR, 0.74, 95% CI, 0.57-0.95) or cryptogenic stroke (OR, 0.82, 95% CI, 0.68-0.98) versus other subtypes; other associations between cryptogenic stroke and speckle tracking echocardiography were not found. Conclusions Markers of LA structure and function were associated with CS. Similar associations were not found for cryptogenic stroke, which might suggest different underlying mechanisms, given study limitations. Further understanding could aid stroke diagnosis and secondary stroke prevention research.

References Values for Left Atrial Volumes, Emptying Fractions, Strains, and Strain Rates and Their Determinants by Age, Gender, and Ethnicity: The Multiethnic Study of Atherosclerosis (MESA).

RATIONALE AND OBJECTIVES: Left Atrial (LA) adverse remodeling is an important predictor of morbidity and mortality in several cardiovascular (CV) diseases. Our goals were to quantify and provide reference ranges for LA structure and function using feature tracking cine cardiac magnetic resonance. MATERIALS AND METHODS: 2526 participants of the Multiethnic Study of Atherosclerosis study who had feature tracking cine cardiac magnetic resonance derived LA data and were free of atrial fibrillation/flutter and prior CV events at year five follow-up examination (2010-2012) were included in this study. LA phasic indexed volumes: maximum (LAVi max), minimum (LAVi min), and preatrial contraction (LAVi preA); LA empty fractions: total, passive, and active (LAtEF, LApEF, and LAaEF); LA longitudinal strain: maximum and preatrial contraction (S max and S preA); and LA longitudinal strain rate: systolic (SR max) and early/late diastolic (SR e and SR a) were measured. Age, gender, and race/ethnicity-specific reference ranges were identified. Also, reference values in a select subgroup of healthy participants free of traditional CV risk factors at the time of exam date were reported. RESULTS: The mean ± SD for LAVi max, LAVi min, LAVi preA, S max, SR e, and SR a were in the 45-65-year-old participants: (33.8 ± 10 mL/m2), (14.5 ± 6.4 mL/m2), (24.8 ± 8.2 mL/m2), (34.6 ± 13.8 %), (-1.4 ± 0.7 s-1), (-2.1 ± 1 s-1) and in the ≥ 65-year-old participants: (35 ± 11.5 mL/m2), (16.6 ± 8.3 mL/m2), (27.6 ± 9.9 mL/m2), (31.2 ± 14.3 %), (-1 ± 0.6 s-1), (-2.1 ± 1 s-1) respectively. Younger individuals had Powered by Editorial Manager and ProduXion Manager from Aries Systems Corporation smaller LA volumes and better LA function compared to their older counterparts. Similar findings were observed in Chinese-Americans as compared to Whites. CONCLUSION: This study provides reference values of LA structure and function parameters from a healthy multiethnic community-based population aged 53-94 years evaluated by FTMRI.

Sex Differences in the Association of Cumulative Body Mass Index from Early Adulthood to Middle Age and Left Atrial Remodeling Evaluated by Three-Dimensional Echocardiography: The Coronary Artery Risk Development in Young Adults Study.

BACKGROUND: The relationship between long-term obesity and left atrial (LA) structure and function is not entirely understood. We examined the association of cumulative body mass index (cBMI) with LA remodeling using three-dimensional (3D) speckle-tracking echocardiography (STE). METHODS: The Coronary Artery Risk Development in Young Adults (CARDIA) study is a community-based cohort of black and white, men and women, ages 18-30 years at baseline in 1985-86 from four U.S. centers. This study included 2,144 participants who had satisfactory image quality and body mass index measurements during the entire follow-up period. The 3D STE-derived LA parameters were maximum, minimum, and pretrial contraction volumes; total, passive, and active emptying fraction; maximum systolic longitudinal strain; and early and late diastolic longitudinal strain rates. Multivariable linear regression analyses stratified by sex assessed the relationship between cBMI and 3D STE-derived LA parameters, adjusting for demographics and traditional cardiovascular. RESULTS: The mean age of the cohort was 55 ± 3.6 years; 54.8% were women, and 46.5% were black. There were statistically significant additive sex interactions for the association between cBMI and LA minimum contraction value, maximum systolic longitudinal strain, and early and late diastolic longitudinal strain rates. In the fully adjusted model, greater cBMI was associated with lower magnitude LA longitudinal deformation (maximum systolic longitudinal strain and early and late diastolic longitudinal strain rates) in men and with higher LA emptying fraction in women. In addition, greater cBMI was associated with higher LA phasic volumes indices in both men and women. CONCLUSIONS: This study showed that while greater cBMI from early adulthood throughout middle age was associated with higher LA volumes in both genders, differences were found for LA function, with lower longitudinal deformation in men and higher reservoir and active LA function in women.