Aspirin use for primary prevention among US adults with and without elevated Lipoprotein(a).

Objective: Lipoprotein(a) [Lp(a)] is an atherogenic and prothrombotic lipoprotein associated with atherosclerotic cardiovascular disease (ASCVD). We assessed the association between regular aspirin use and ASCVD mortality among individuals with versus without elevated Lp(a) in a nationally representative US cohort. Methods: Eligible participants were aged 40-70 years without clinical ASCVD, reported on aspirin use, and had Lp(a) measurements from the Third National Health and Nutrition Examination Survey (NHANES III, 1988-1994), the only cycle of this nationally representative US cohort to measure Lp(a). Regular aspirin use was defined as taking aspirin ≥30 times in the previous month. Using NHANES III linked mortality records and weighted Cox proportional hazards regression, the association between regular aspirin use and ASCVD mortality was observed in those with and without elevated Lp(a) (≥50 versus <50 mg/dL) over a median 26-year follow-up. Results: Among 2,990 persons meeting inclusion criteria (∼73 million US adults), the mean age was 50 years, 86% were non-Hispanic White, 9% were non-Hispanic Black, 53% were female, and 7% reported regular aspirin use. The median Lp(a) was 14 mg/dL and the proportion with elevated Lp(a) was similar among those with versus without regular aspirin use (15.1% versus 21.9%, p = 0.16). Among individuals with elevated Lp(a), the incidence of ASCVD mortality per 1,000 person-years was lower for those with versus without regular aspirin use (1.2, 95% CI: 0.1-2.3 versus 3.9, 95% CI: 2.8-4.9). In multivariable modeling, regular aspirin use was associated with a 52% lower risk of ASCVD mortality among individuals with elevated Lp(a) (HR=0.48, 95% CI: 0.28-0.83), but not for those without elevated Lp(a) (HR=1.01, 95% CI: 0.81-1.25; p-interaction=0.001). Conclusion: Regular aspirin use was associated with significantly lower ASCVD mortality in adults without clinical ASCVD who had elevated Lp(a). These findings may have clinical and public health implications for aspirin utilization in primary prevention.

Association of apolipoprotein B and apolipoprotein A1 levels with social determinants of health and coronary artery disease mortality in the United Kingdom Biobank - is there a need for consideration?

BACKGROUND: A higher prevalence of cardiovascular risk factors has previously been shown to be associated with adverse social determinants of health (SDoH) and to explain some of their impact on cardiovascular risk. Whether there is a relationship between lipid parameters, specifically apolipoprotein B (apoB), apolipoprotein A1 (apoA1), their ratio (apoB/apoA1), and SDoH, and whether coronary artery disease (CAD) mortality risk associated with circulating apoB and apoA1 is modified by SDoH was unclear. METHODS: We investigated associations of apoA1, apoB, and apoB/apoA1 with the level of education and household income and their joint impact on CAD mortality in participants of the UK Biobank (UKB) with and without prevalent CAD at enrollment. Hazard ratios for CAD mortality were estimated after adjusting for SDoH and clinical covariates. RESULTS: In 292 804 participants without established CAD, apoB, and the apoB/apoA1 ratio were inversely associated with level of education and household income, whereas apoA1 was positively associated with household income. Adjustment for education level and household income coupled with the number of people living in the household did not attenuate the association between the apolipoprotein levels and incident CAD mortality rates. In a cohort of 13 826 participants with prevalent CAD, apoA1 levels were inversely associated with level of education. Higher apoB levels were only associated with greater CAD mortality risk after adjustment for risk factors. Risk estimation for CAD death through circulating apoA1 levels requires accounting for significant differences by sex. CONCLUSION: Circulating lipid parameters are associated with SDoH in individuals without CAD. CAD mortality risk estimation through apoA1 and apoB levels does not require accounting for SDoH.

Inhibition of superoxide and iNOS augment cutaneous nitric oxide-dependent vasodilation in non-Hispanic black young adults.

We assessed the combined effect of superoxide and iNOS inhibition on microvascular function in non-Hispanic Black and non-Hispanic White participants (n = 15 per group). Participants were instrumented with four microdialysis fibers: (1) lactated Ringer's (control), (2) 10 µM tempol (superoxide inhibition), (3) 0.1 mM 1400 W (iNOS inhibition), (4) tempol + 1400 W. Cutaneous vasodilation was induced via local heating and NO-dependent vasodilation was quantified. At control sites, NO-dependent vasodilation was lower in non-Hispanic Black (45 ± 9% NO) relative to non-Hispanic White (79 ± 9% NO; p < 0.01; effect size, d = 3.78) participants. Tempol (62 ± 16% NO), 1400 W (78 ± 12% NO) and tempol +1400 W (80 ± 13% NO) increased NO-dependent vasodilation in non-Hispanic Black participants relative to control sites (all p < 0.01; d = 1.22, 3.05, 3.03, respectively). The effect of 1400 W (p = 0.04, d = 1.11) and tempol +1400 W (p = 0.03, d = 1.22) was greater than tempol in non-Hispanic Black participants. There was no difference between non-Hispanic Black and non-Hispanic White participants at 1400 W or tempol + 1400 W sites. These data suggest iNOS has a greater effect on NO-dependent vasodilation than superoxide in non-Hispanic Black participants.

Hemodynamic Reactivity to Mental Stress and Cognitive Function in Coronary Artery Disease.

OBJECTIVE: People with coronary artery disease (CAD) are at higher risk of cognitive impairment than those without CAD. Psychological stress is a risk factor for both conditions and assessing the hemodynamic reactivity to mental stress could explain the link between stress and cognitive function. METHODS: Individuals with stable CAD from two prospective cohort studies were included. All individuals underwent acute mental stress testing, as well as conventional stress testing. Cognitive function was assessed both at baseline and at a 2-year follow-up. The rate-pressure product (RPP) was calculated as the mean systolic blood pressure times the mean heart rate at rest. RPP reactivity was defined as the maximum RPP during standardized mental stress test minus the RPP at rest. RESULTS: After multivariable adjustment, every standard deviation decrease in RPP reactivity with mental stress was associated with slower completion of Trail-A and Trail-B in both cohorts (13% and 11% in cohort 1, and 15% and 16% in cohort 2, respectively, p for all <0.01). After a 2-year follow-up period, every standard deviation decrease in RPP reactivity with mental stress was associated with a 8%, and 9% slower completion of Trail-A and Trail-B, respectively (p for all <0.01). There was no significant association between RPP reactivity with conventional stress testing and any of the cognitive tests. CONCLUSION: In the CAD population, a blunted hemodynamic response to mental stress is associated with slower visuomotor processing and worse executive function at baseline and with greater decline in these abilities over time.

Heart-brain axis: pushing the boundaries of cardiovascular molecular imaging.

Despite decades of research, the heart-brain axis continues to challenge investigators seeking to unravel its complex pathobiology. Strong epidemiologic evidence supports a link by which insult or injury to one of the organs increases the risk of pathology in the other. The putative pathways have important differences between sexes and include alterations in autonomic function, metabolism, inflammation, and neurohormonal mechanisms that participate in crosstalk between the heart and brain and contribute to vascular changes, the development of shared risk factors, and oxidative stress. Recently, given its unique ability to characterize biological processes in multiple tissues simultaneously, molecular imaging has yielded important insights into the interplay of these organ systems under conditions of stress and disease. Yet, additional research is needed to probe further into the mechanisms underlying the heart-brain axis and to evaluate the impact of targeted interventions.

Circulating Progenitor Cells and Coronary Collaterals in Chronic Total Occlusion.

BACKGROUND: The role of circulating progenitor cells (CPC) in collateral formation that occurs in the presence of chronic total occlusions (CTO) of a coronary artery is not well established. In stable patients with a CTO, we investigated whether CPC levels are associated with (a) collateral development and (b) ischemic burden, as measured by circulating high sensitivity troponin-I (hsTn-I) levels. METHODS: CPCs were enumerated by flow cytometry as CD45med+ blood mononuclear cells expressing CD34 and both CD34 and CD133 epitopes. The association between CPC counts and both Rentrop collateral grade (0, 1, 2, or 3) and hsTn-I levels were evaluated using multivariate regression analysis, after adjusting for demographic and clinical characteristics. RESULTS: In 89 patients (age 65.5, 72% male, 27% Black), a higher CPC count was positively associated with a higher Rentrop collateral grade; [CD34+ adjusted odds ratio (OR) 1.49 95% confidence interval (CI) (0.95, 2.34) P = 0.082] and [CD34+/CD133+ OR 1.57 95% CI (1.05, 2.36) P = 0.028]. Every doubling of CPC counts was also associated with lower hsTn-I levels [CD34+ ß -0.35 95% CI (-0.49, -0.15) P = 0.002] and [CD34+/CD133+ ß -0.27 95% CI (-0.43, -0.08) P = 0.009] after adjustment. CONCLUSION: Individuals with higher CPC counts have greater collateral development and lower ischemic burden in the presence of a CTO.

Intra- and inter-reader reproducibility in quantitative coronary plaque analysis on coronary computed tomography angiography.

PURPOSE: Coronary artery plaque burden, low attenuation non-calcified plaque (LAP), and pericoronary adipose tissue (PCAT) on coronary CT angiography (CCTA), have been linked to future cardiac events. The purpose of this study was to evaluate intra- and inter reader reproducibility in the quantification of coronary plaque burden and its characteristics using an artificial intelligence-enhanced semi-automated software. MATERIALS AND METHODS: A total of 10 women and 6 men, aged 52 (IQR 49-58) underwent CCTA using a Siemens Somatom Force, Somatom Definition AS and Somatom Definition Flash scanners. Two expert readers utilized dedicated semi-automatic software (vascuCAP, Elucid Bioimaging, Wenham, MA) to assess calcified plaque, low attenuation plaque and PCAT. Readers were blinded to all clinical information and repeated their analysis at 6 weeks in random order to minimize recall bias. Data analysis was performed on the right and left coronary arteries. Intra- and inter-reader reproducibility was compared using Pearson correlation coefficient, while absolute values between analyses and readers were compared with paired non-parametric tests. This is a sub-study of the Specialized Center of Research Excellence (SCORE) clinical trial (5U54AG062334). RESULTS: A total of 64 vessels from 16 patients were analyzed. Intra-reader Pearson correlation coefficients for calcified plaque volume, LAP volume and PCAT volumes were 0.96, 0.99 and 0.92 for reader 1 and 0.94, 0.94 and 0.95 for reader 2, respectively, (all p < 0.0001). Inter-reader Pearson correlation coefficients for calcified plaque volume, LAP and PCAT volumes were 0.92, 0.96 and 0.78, and 0.99, 0.99 and 0.93 on the second analyses, all had a p value <0.0001. There was no significant bias on the corresponding Bland-Altman analyses. CONCLUSION: Volume measurement of coronary plaque burden and PCAT volume can be performed with high intra- and inter-reader agreement.

Liver and cardiovascular disease outcomes in metabolic syndrome and diabetic populations: Bi-directional opportunities to multiply preventive strategies.

The incidence and prevalence of metabolic syndrome (MetS) and type 2 diabetes mellitus (T2DM) are rising globally. MetS and T2DM are associated with significant morbidity and mortality, which is partly related to liver and cardiovascular disease. Insulin resistance is central to MetS and T2DM pathophysiology, and drives ectopic fat deposition in the liver, also known as metabolic dysfunction-associated steatotic liver disease (MASLD). MetS and T2DM are not only risk factors for developing MASLD but are also independently associated with disease progression to steatohepatitis, cirrhosis, and hepatocellular carcinoma. In addition to the risk of liver disease, MetS and T2DM are independent risk factors for cardiovascular disease (CVD), including coronary artery disease (CAD) and heart failure (HF). Importantly, there is a bidirectional relationship between liver and CVD due to shared disease pathophysiology in patients with MetS and T2DM. In this review, we have described studies exploring the relationship of MetS and T2DM with MASLD and CVD, independently. Following this we discuss studies evaluating the interplay between liver and cardiovascular risk as well as pragmatic risk mitigation strategies in this patient population.

Restless legs syndrome, periodic limb movements of sleep, and subclinical cardiovascular disease.

Restless legs syndrome (RLS) and periodic limb movements of sleep (PLMS) have been variably implicated in risk for cardiovascular disease (CVD), but there is lack of consensus on these relationships. We sought to assess subclinical CVD measures and RLS/PLMS in a large cohort to further evaluate these associations. The Emory Center for Health Discovery and Well Being cohort is composed of employed adults, with subclinical CVD measures including endothelial function (flow-mediated vasodilation), microvascular function (reactive hyperemia index, RHI), arterial stiffness (pulse wave velocity and augmentation index), and carotid intima-media thickness (cIMT). Participants were grouped based on presence (N = 50) or absence (N = 376) of RLS and subclinical CVD measures compared between groups. A subset of participants (n = 40) underwent ambulatory monitoring for PLMS and obstructive sleep apnea. PLMS association with subclinical CVD measures was assessed. RLS status was significantly associated with flow-mediated dilation in univariate analyses but not after controlling for potential confounders; RLS was not associated with other subclinical CVD measures. PLMS were significantly correlated with the RHI, augmentation index, and cIMT in univariate analyses; only the association between PLMS and cIMT remained significant (p = 0.04) after controlling for RLS status, age, apnea-hypopnea index, hyperlipidemia, and hypertension. The observed association between higher PLMS and greater cIMT suggests that PLMS may be a marker of subclinical CVD. Further work is needed to determine the relationship between PLMS and CVD risk. Supplementary Information: The online version contains supplementary material available at 10.1007/s41105-023-00497-7.

Psychological Distress and the Risk of Adverse Cardiovascular Outcomes in Patients With Coronary Heart Disease.

BACKGROUND: Psychological distress is a recognized risk factor in patients with coronary heart disease (CHD), but its clinical significance is unclear. OBJECTIVES: The purpose of this study was to determine if an index of psychological distress is independently associated with adverse outcomes and significantly contributes to risk prediction. METHODS: Pooled analysis of 2 prospective cohort studies of patients with stable CHD (N = 891). A psychological distress score was constructed using measures of depression, anxiety, anger, perceived stress, and post-traumatic stress disorder, measured at baseline. The study endpoint included cardiovascular death or first or recurrent nonfatal myocardial infarction or hospitalization for heart failure at 5.9 years. RESULTS: In both cohorts, first and recurrent events occurred more often among those in the highest tertile of distress score than those in the lowest tertile. After combining the 2 cohorts, compared with the lowest tertile, the hazards ratio for having a distress score in the highest tertile was 2.27 (95% CI: 1.69-3.06), and for the middle tertile, it was 1.52 (95% CI: 1.10-2.08). Adjustment for demographics and clinical risk factors only slightly weakened the associations. When the distress score was added to a traditional clinical risk model, C-statistic, net reclassification index, and integrative discrimination index all significantly improved. CONCLUSIONS: Among patients with CHD, a composite measure of psychological distress was significantly associated with an increased risk of adverse events and significantly improved risk prediction.

Left Main Coronary Artery Calcium and Diabetes Confer Very-High-Risk Equivalence in Coronary Artery Calcium >1,000.

BACKGROUND: Although a coronary artery calcium (CAC) of ≥1,000 is a subclinical atherosclerosis threshold to consider combination lipid-lowering therapy, differentiating very high from high atherosclerotic cardiovascular disease (ASCVD) risk in this patient population is not well-defined. OBJECTIVES: Among persons with a CAC of ≥1,000, the authors sought to identify risk factors equating with very high-risk ASCVD mortality rates. METHODS: The authors studied 2,246 asymptomatic patients with a CAC of ≥1,000 from the CAC Consortium without a prior ASCVD event. Cox proportional hazards regression modelling was performed for ASCVD mortality during a median follow-up of 11.3 years. Crude ASCVD mortality rates were compared with those reported for secondary prevention trial patients classified as very high risk, defined by ≥2 major ASCVD events or 1 major event and ≥2 high-risk conditions (1.4 per 100 person-years). RESULTS: The mean age was 66.6 years, 14% were female, and 10% were non-White. The median CAC score was 1,592 and 6% had severe left main (LM) CAC (vessel-specific CAC ≥300). Diabetes (HR: 2.04 [95% CI: 1.47-2.83]) and severe LM CAC (HR: 2.32 [95% CI: 1.51-3.55]) were associated with ASCVD mortality. The ASCVD mortality per 100 person-years for all patients was 0.8 (95% CI: 0.7-0.9), although higher rates were observed for diabetes (1.4 [95% CI: 0.8-1.9]), severe LM CAC (1.3 [95% CI: 0.6-2.0]), and both diabetes and severe LM CAC (7.1 [95% CI: 3.4-10.8]). CONCLUSIONS: Among asymptomatic patients with a CAC of ≥1,000 without a prior index event, diabetes, and severe LM CAC define very high risk ASCVD, identifying individuals who may benefit from more intensive prevention therapies across several domains, including low-density lipoprotein-cholesterol lowering.

Long-Term Outcomes in Patients With Chronic Total Occlusion.

Although a chronic total occlusion (CTO) in the setting of an acute coronary syndrome is associated with greater risk, the prognosis of patients with a CTO and stable coronary artery disease (CAD) remains unknown. This study aimed to investigate adverse event rates in patients with stable CAD with and without a CTO. In 3,597 patients with stable CAD (>50% coronary luminal stenosis) who underwent cardiac catheterization, all-cause mortality, cardiovascular mortality, and the composite major adverse cardiac event (MACE) rates for cardiovascular death, myocardial infarction, and heart failure hospitalization were evaluated. Cox proportional hazards and Fine and Gray subdistribution hazard models were used to compare event-free survival in patient subsets after adjustment for covariates. Event rates were higher in patients with CTOs than in those without CTOs after adjusting for demographic and clinical characteristics (cardiovascular death hazard ratio [HR] 1.29, 95% confidence interval [CI] 1.05 to 1.57, p = 0.012). Patients with CTO revascularization had lower event rates than those of patients without CTO revascularization (cardiovascular death HR 0.43, CI 0.26 to 0.70, p = 0.001). Those with nonrevascularized CTOs were at particularly great risk when compared with those without CTO (cardiovascular death HR 1.52, CI 1.25 to 1.84, p <0.001). Moreover, those with revascularized CTOs had similar event rates to those of patients with CAD without CTOs. Patients with CTO have higher rates of adverse cardiovascular events than those of patients with significant CAD without CTO. This risk is greatest in patients with nonrevascularized CTO.

Factors Associated With Fatigue in Persons With Atrial Fibrillation in the Atherosclerosis Risk in Communities (ARIC) Study.

BACKGROUND: Atrial fibrillation (AF) is a common cardiac arrhythmia affecting over 6 million people in the U.S. Fatigue is a frequent symptom of AF, yet no underlying biological mechanisms have been identified in AF-related fatigue as in other chronic conditions such as cancer or HIV fatigue (inflammation, tissue injury). We aimed to identify biomarkers and correlates of AF-fatigue in ARIC participants. METHODS: Participants with AF from ARIC visit 5 (2011-2013) were included in the study. Multiple linear regression was used to estimate the association of high sensitivity troponin (hs-TnT), N-terminal fragment B-type natriuretic peptide (NT-proBNP) and high sensitivity C-reactive protein (hsCRP) levels with self-reported fatigue (SF-12 and PROMIS Fatigue Scale), depressive symptoms (Center for Epidemiological Studies Depression survey), and physical functioning (Short Physical Performance Battery) scores. All biomarkers underwent natural-log transformation. RESULTS: There were 446 participants (mean age: 78 y ± 5; 44% women). In adjusted analyses, NT-proBNP was associated with AF-fatigue (ß: 0.11, 95% CI: 0.03, 0.19), increased depressive symptoms (ß: 0.44, 95% CI: 0.19, 0.70), and decreased physical function (ß: -0.48, 95% CI: -0.72, -0.23). Hs-TnT was also associated with elevated AF-fatigue (ß: 0.24, 95% CI: 0.09, 0.39) along with decreased physical function (ß: -1.19, 95% CI: -1.64, -0.75). No significant associations were found with hsCRP and fatigue. CONCLUSION: Increased levels of cardiac injury biomarkers, depressive symptoms, and decreased physical function were associated with AF-fatigue. Inflammation was not associated with AF-fatigue; other physiological pathways, such as cardiac overload or myocardial injury may be more relevant in AF-fatigue.

Acute psychological stress-induced progenitor cell mobilization and cardiovascular events.

OBJECTIVE: Certain brain activation responses to psychological stress are associated with worse outcomes in CVD patients. We hypothesized that elevated acute psychological stress, manifesting as greater activity within neural centers for emotional regulation, mobilizes CPC from the bone marrow to the peripheral blood and predicts future cardiovascular events. METHODS: In 427 patients with stable CAD undergoing a laboratory-based mental stress (MS) test, CPCs were enumerated using flow cytometry as CD34-expressing mononuclear cells (CD34+) before and 45 min after stress. Changes in brain regional blood flow with MS were measured using high resolution-positron emission tomography (HR-PET). Association between the change in CPC with MS and the risk of cardiovascular death or myocardial infarction (MI) during a 5-year follow-up period was analyzed. RESULTS: MS increased CPC counts by a mean of 150 [630] cells/mL (15%), P < 0.001. Greater limbic lobe activity, indicative of activation of emotion-regulating centers, was associated with greater CPC mobilization (P < 0.005). Using Fine and Gray models after adjustment for demographioc, clinical risk factors and medications use, greater CPC mobilization was associated with a higher adjusted risk of adverse events; a rise of 1000 cells/mL was associated with a 50% higher risk of cardiovascular death/MI [hazards ratio, 1.5, 95% confidence interval, 1.1-2.2). CONCLUSION: Greater limbic lobe activity, brain areas involved in emotional regulation, is associated with MS-induced CPC mobilization. This mobilization isindependently associated with cardiovascular events. These findings provide novel insights into mechanisms through which psychological stressors modulate cardiovascular risk.

Metabolomic signatures of ideal cardiovascular health in black adults.

Plasma metabolomics profiling is an emerging methodology to identify metabolic pathways underlying cardiovascular health (CVH). The objective of this study was to define metabolomic profiles underlying CVH in a cohort of Black adults, a population that is understudied but suffers from disparate levels of CVD risk factors. The Morehouse-Emory Cardiovascular (MECA) Center for Health Equity study cohort consisted of 375 Black adults (age 53 ± 10, 39% male) without known CVD. CVH was determined by the AHA Life's Simple 7 (LS7) score, calculated from measured blood pressure, body mass index (BMI), fasting blood glucose and total cholesterol, and self-reported physical activity, diet, and smoking. Plasma metabolites were assessed using untargeted high-resolution metabolomics profiling. A metabolome wide association study (MWAS) identified metabolites associated with LS7 score after adjusting for age and sex. Using Mummichog software, metabolic pathways that were significantly enriched in metabolites associated with LS7 score were identified. Metabolites representative of these pathways were compared across clinical domains of LS7 score and then developed into a metabolomics risk score for prediction of CVH. We identified novel metabolomic signatures and pathways associated with CVH in a cohort of Black adults without known CVD. Representative and highly prevalent metabolites from these pathways included glutamine, glutamate, urate, tyrosine and alanine, the concentrations of which varied with BMI, fasting glucose, and blood pressure levels. When assessed in conjunction, these metabolites were independent predictors of CVH. One SD increase in the novel metabolomics risk score was associated with a 0.88 higher LS7 score, which translates to a 10.4% lower incident CVD risk. We identified novel metabolomic signatures of ideal CVH in a cohort of Black Americans, showing that a core group of metabolites central to nitrogen balance, bioenergetics, gluconeogenesis, and nucleotide synthesis were associated with CVH in this population.

Does Elevated High-Density Lipoprotein Cholesterol Protect Against Cardiovascular Disease?

High-density lipoprotein (HDL) contributes to reverse cholesterol transport, which is 1 of the main explanations for the described inverse association between HDL-cholesterol (HDL-C) and atherosclerotic cardiovascular disease (ASCVD) risk. However, efforts to therapeutically raise HDL-C levels with niacin, fibrates, or cholesteryl ester transfer protein inhibitors have not demonstrated a reduction in ASCVD events when compared with placebo among individuals treated with statins. Furthermore, mendelian randomization studies suggest that HDL-C is unlikely to be a direct biologic variable impacting ASCVD risk. More recently, observations from well-conducted epidemiologic studies have indicated a nonlinear U-shaped relationship between HDL-C and subclinical atherosclerosis, and that very high HDL-C (≥80 mg/dL in men, ≥100 mg/dL in women) is paradoxically associated with higher all-cause and ASCVD-related mortality. These observations suggest that HDL-C is not a universal protective factor for atherosclerosis. Thus, there are several opportunities for reframing the contribution of HDL-C to ASCVD risk and related clinical calculators. Here, we examine our growing understanding of HDL-C and its role in ASCVD risk assessment, treatment, and prevention. We discuss the biological functions of HDL-C and its normative values in relation to demographics and lifestyle markers. We then summarize original studies that observed a protective association between HDL-C and ASCVD risk and more recent evidence indicating an elevated ASCVD risk at very high HDL-C levels. Through this process, we advance the discussion regarding the future role of HDL-C in ASCVD risk assessment and identify knowledge gaps pertaining to the precise role of HDL-C in atherosclerosis and clinical ASCVD.

Soluble urokinase Plasminogen Activator Receptor (suPAR) mediates the effect of a lower education level on adverse outcomes in patients with coronary artery disease.

AIMS: To investigate whether the adverse impact of lower educational attainment on mortality risk in patients with coronary artery disease (CAD) is mediated by the activation of inflammatory and immune pathways, estimated as elevated soluble urokinase plasminogen activator receptor levels. METHODS AND RESULTS: In 3164 patients undergoing coronary angiography, we investigated multivariable associations between suPAR and educational attainment and assessed the relationship between a lower educational level (defined as a high-school degree or less as the highest educational qualification) and outcomes using Cox proportional hazard and Fine and Gray's subdistribution competing risk models. The potential mediating effect through suPAR and high-sensitivity C-reactive protein (hs-CRP) was assessed using mediation analysis. A total of 1814 patients (57.3%) had achieved a higher (≥college) education level and 1350 patients (42.7%) a lower (≤high school) education level. Soluble urokinase plasminogen activator receptor levels were 9.0% [95% confidence interval (CI) 6.3-11.8, P ≤ 0.0001] higher in patients with lower educational qualifications than in those with higher educational qualifications after covariate adjustment. Lower educational attainment was associated with a higher risk of cardiovascular death after adjustment for demographic, clinical, and behavioural covariates, including CAD severity and heart failure history, medication use, and hs-CRP levels [hazard ratio 1.26 (95% CI 1.02-1.55, P = 0.03)]. However, after adjustment for suPAR levels, the effect of a lower educational level on cardiovascular death became insignificant. Values were similar for all-cause death. Soluble urokinase plasminogen activator receptor levels mediated 49% and hs-CRP levels 17% of the cardiovascular death risk attributable to lower educational attainment. CONCLUSION: Circulating suPAR levels importantly mediate the effects of lower educational attainment on mortality, indicating the importance of systemic inflammation and immune dysregulation as biologic mediators of adverse social determinants of health.

In patients with coronary artery disease (CAD), we demonstrate that nearly half of the higher risk of all-cause and cardiovascular mortality associated with lower educational attainment as a measure of socioeconomic status is mediated by systemic inflammation and immune dysregulation, which can be estimated by measuring the circulating soluble urokinase plasminogen activator receptor (suPAR) levels. Even after accounting for differences in cardiovascular risk factors, lower educational attainment is associated with higher mortality risk in patients with CAD and there is activation of inflammatory pathways and immune dysregulation in those with lower (≤high school) educational attainment than in those with higher (≥college) educational attainment, estimated as higher circulating suPAR levels.Almost half of the higher risk for adverse outcomes observed in those with lower educational attainment appears to be due to systemic inflammation and immune dysregulation and can be estimated from measuring suPAR levels.

Hypoglossal Nerve Stimulation and Cardiovascular Outcomes for Patients With Obstructive Sleep Apnea: A Randomized Clinical Trial.

Importance: Sham-controlled trials are needed to characterize the effect of hypoglossal nerve stimulation (HGNS) therapy on cardiovascular end points in patients with moderate-severe obstructive sleep apnea (OSA). Objective: To determine the effect of therapeutic levels of HGNS, compared to sham levels, on blood pressure, sympathetic activity, and vascular function. Design, Setting, and Participants: This double-blind, sham-controlled, randomized crossover therapy trial was conducted from 2018 to 2022 at 3 separate academic medical centers. Adult patients with OSA who already had an HGNS device implanted and were adherent and clinically optimized to HGNS therapy were included. Participants who had fallen asleep while driving within 1 year prior to HGNS implantation were excluded from the trial. Data analysis was performed from January to September 2022. Interventions: Participants underwent a 4-week period of active HGNS therapy and a 4-week period of sham HGNS therapy in a randomized order. Each 4-week period concluded with collection of 24-hour ambulatory blood pressure monitoring (ABPM), pre-ejection period (PEP), and flow-mediated dilation (FMD) values. Main Outcomes and Measures: The change in mean 24-hour systolic blood pressure was the primary outcome, with other ABPM end points exploratory, and PEP and FMD were cosecondary end points. Results: Participants (n = 60) were older (mean [SD] age, 67.3 [9.9] years), overweight (mean [SD] body mass index, calculated as weight in kilograms divided by height in meters squared, 28.7 [4.6]), predominantly male (38 [63%]), and had severe OSA at baseline (mean [SD] apnea-hypopnea index, 33.1 [14.9] events/h). There were no differences observed between active and sham therapy in 24-hour systolic blood pressure (mean change on active therapy, -0.18 [95% CI, -2.21 to 1.84] mm Hg), PEP (mean change on active therapy, 0.11 [95% CI, -5.43 to 5.66] milliseconds), or FMD (mean change on active therapy, -0.17% [95% CI, -1.88% to 1.54%]). Larger differences between active and sham therapy were observed in a per-protocol analysis set (n = 20) defined as experiencing at least a 50% reduction in apnea-hypopnea index between sham and active treatment. Conclusions and Relevance: In this sham-controlled HGNS randomized clinical trial, mean 24-hour systolic blood pressure and other cardiovascular measures were not significantly different between sham and active HGNS therapy. Several methodologic lessons can be gleaned to inform future HGNS randomized clinical trials. Trial Registration: ClinicalTrials.gov Identifier: NCT03359096.

High sensitivity troponin I as a biomarker for cardiac allograft vasculopathy: Evaluation of diagnostic potential and clinical utility.

INTRODUCTION: Cardiac allograft vasculopathy (CAV) limits long-term survival in heart transplant (HTx) recipients. The use of biomarkers in CAV surveillance has been studied, but none are used in clinical practice. The predictive value of high-sensitivity troponin I (hsTnI) has not been extensively investigated in HTx recipients. METHODS: HTx patients undergoing surveillance coronary angiograms and enrolled in the Emory Cardiovascular Biobank had plasma hsTnI measured. CAV grade was assessed using ISHLT nomenclature. Multivariable cumulative link mixed modeling was performed to determine association between hsTnI level and CAV grade. Patients were followed for adverse outcomes over a median 10-year period. Kaplan-Meier survival analysis and Cox proportional hazard modeling were performed. RESULTS: Three hundred and seventy-two angiograms were analyzed in 156 patients at a median 8.9 years after transplant. hsTnI levels were positively correlated with concurrent CAV grade after adjustment for age, age at transplant, sex, BMI, hypertension, diabetes, hyperlipidemia, estimated glomerular filtration rate, and history of acute cellular rejection (p = .016). In an adjusted Cox proportional hazard model, initial hsTnI level above the median (4.9 pg/mL) remained a predictor of re-transplantation or death (hazard ratio 1.82; 95% confidence interval 1.16-2.90; p = .01). CONCLUSION: An elevated hsTnI level reflects severity of CAV and is associated with poor long-term outcomes in patients with HTx.