Sex Differences in Vascular Response to Mental Stress and Adverse Cardiovascular Events Among Patients With Ischemic Heart Disease.

BACKGROUND: Microvascular measures of vascular dysfunction during acute mental stress may be important determinants of major adverse cardiovascular events (MACE), especially among younger and middle-aged women survivors of an acute myocardial infarction. METHODS: In the MIMS2 study (Myocardial Infarction and Mental Stress 2), individuals who had been hospitalized for a myocardial infarction in the past 8 months were prospectively followed for 5 years. MACE was defined as a composite index of cardiovascular death and first/recurring events for nonfatal myocardial infarction and hospitalizations for heart failure. Reactive hyperemia index and flow-mediated dilation were used to measure microvascular and endothelial function, respectively, before and 30 minutes after a public-speaking mental stress task. Survival models for recurrent events were used to examine the association between vascular response to stress (difference between poststress and resting values) and MACE. Reactive hyperemia index and flow-mediated dilation were standardized in analyses. RESULTS: Of 263 patients (the mean age was 51 years; range, 25-61), 48% were women, and 65% were Black. During a median follow-up of 4.3 years, 64 patients had 141 adverse cardiovascular events (first and repeated). Worse microvascular response to stress (for each SD decrease in the reactive hyperemia index) was associated with 50% greater risk of MACE (hazard ratio, 1.50 [95% CI, 1.05-2.13]; P=0.03) among women only (sex interaction: P=0.03). Worse transient endothelial dysfunction in response to stress (for each SD decrease in flow-mediated dilation) was associated with a 35% greater risk of MACE (hazard ratio, 1.35 [95% CI, 1.07-1.71]; P=0.01), and the association was similar in women and men. CONCLUSIONS: Peripheral microvascular dysfunction with mental stress was associated with adverse events among women but not men. In contrast, endothelial dysfunction was similarly related to MACE among both men and women. These results suggest a female-specific mechanism linking psychological stress to adverse outcomes.

Soluble Urokinase Plasminogen Activator Receptor Levels and Outcomes in Patients with Heart Failure.

BACKGROUND: Soluble urokinase-type plasminogen activator receptor (suPAR) is a marker of immune activation and pathogenic factor for kidney disease shown to predict cardiovascular outcomes including heart failure (HF) in various populations. We characterized suPAR levels in patients with HF and compared its ability to discriminate risk to that of B-type natriuretic peptide (BNP). METHODS AND RESULTS: We measured plasma suPAR and BNP levels in 3,437 patients undergoing coronary angiogram and followed for a median of 6.2 years. We performed survival analyses for the following outcomes: all-cause death, cardiovascular death, and hospitalization for HF. We then assessed suPAR's ability to discriminate risk for the aforementioned outcomes. We identified 1116 patients with HF (age 65±12, 67.2% male, 20.0% Black, 67% with reduced ejection fraction). The median suPAR level was higher in HF compared to those without HF (3370 [IQR 2610-4371] vs. 2880 [IQR 2270-3670] pg/mL, respectively, P<0.001). In patients with HF, suPAR levels (log-base 2) were associated with outcomes including all-cause death (adjusted hazard ratio aHR 2.30, 95%CI[1.90-2.77]), cardiovascular death (aHR 2.33 95%CI[1.81-2.99]) and HF hospitalization (aHR 1.96, 95%CI[1.06-1.25]) independently of clinical characteristics and BNP levels. The association persisted across subgroups and did not differ between patients with reduced or preserved ejection fraction, or those with ischemic or non-ischemic cardiomyopathy. Addition of suPAR to a model including BNP levels significantly improved the C-statistic for death (Δ0.027), cardiovascular death (Δ0.017) and hospitalization for HF (Δ0.017). CONCLUSIONS: SuPAR levels are higher in HF compared to non-HF, are strongly predictive of outcomes, and combined with BNP, significantly improved risk prediction.

Vascular Regenerative Capacity and the Obesity Paradox in Coronary Artery Disease.

[Figure: see text].

Peripheral Vasoconstriction During Mental Stress and Adverse Cardiovascular Outcomes in Patients With Coronary Artery Disease.

RATIONALE: Excessive vasoconstriction in response to mental stress may be a potential mechanism by which acute psychological stress leads to adverse cardiac events. OBJECTIVES: We investigated whether excessive digital vasoconstriction during acute mental stress predicts adverse cardiovascular outcomes among patients with coronary artery disease. METHODS AND RESULTS: Five hundred forty-nine patients with stable coronary artery disease (age 63±9, 76% male, 29% black) underwent mental stress testing with a standardized public speaking stressor and followed prospectively for cardiovascular end points. Digital pulse wave amplitude was continuously measured using peripheral artery tonometry (PAT, Itamar Inc). Stress/rest PAT ratio (sPAT) of pulse wave amplitude during mental stress/baseline was calculated and dichotomized by the median value into low and high sPAT ratio groups. Upon 3-year follow-up, Fine and Gray's subdistribution hazard ratios were used to examine the association between sPAT ratio and the composite end point of cardiovascular death, myocardial infarction, revascularization, and hospitalization for heart failure. The median sPAT ratio was 0.68 (interquartile range, 0.48-0.88), indicating 32% vasoconstriction with mental stress. Men were more likely to have low sPAT ratio than women (odds ratio, 1.79; P=0.007) while those on ß-blockers were less likely to have low sPAT ratio (odds ratio, 0.52; P=0.003). After adjusting for demographic and cardiovascular risk factors, medications, and rate-pressure product change during mental stress, those with low sPAT ratio were at significantly higher risk of adverse outcomes (subdistribution hazard ratio, 1.77 [95% CI, 1.12-2.80]). CONCLUSIONS: Greater peripheral vasoconstriction with mental stress, denoted by a low sPAT ratio, is associated with a higher risk of adverse cardiovascular outcomes in patients with coronary artery disease.

Association of Mental Stress-Induced Myocardial Ischemia With Cardiovascular Events in Patients With Coronary Heart Disease.

Importance: Mental stress-induced myocardial ischemia is a recognized phenomenon in patients with coronary heart disease (CHD), but its clinical significance in the contemporary clinical era has not been investigated. Objective: To compare the association of mental stress-induced or conventional stress-induced ischemia with adverse cardiovascular events in patients with CHD. Design, Setting, and Participants: Pooled analysis of 2 prospective cohort studies of patients with stable CHD from a university-based hospital network in Atlanta, Georgia: the Mental Stress Ischemia Prognosis Study (MIPS) and the Myocardial Infarction and Mental Stress Study 2 (MIMS2). Participants were enrolled between June 2011 and March 2016 (last follow-up, February 2020). Exposures: Provocation of myocardial ischemia with a standardized mental stress test (public speaking task) and with a conventional (exercise or pharmacological) stress test, using single-photon emission computed tomography. Main Outcomes and Measures: The primary outcome was a composite of cardiovascular death or first or recurrent nonfatal myocardial infarction. The secondary end point additionally included hospitalizations for heart failure. Results: Of the 918 patients in the total sample pool (mean age, 60 years; 34% women), 618 participated in MIPS and 300 in MIMS2. Of those, 147 patients (16%) had mental stress-induced ischemia, 281 (31%) conventional stress ischemia, and 96 (10%) had both. Over a 5-year median follow-up, the primary end point occurred in 156 participants. The pooled event rate was 6.9 per 100 patient-years among patients with and 2.6 per 100 patient-years among patients without mental stress-induced ischemia. The multivariable adjusted hazard ratio (HR) for patients with vs those without mental stress-induced ischemia was 2.5 (95% CI, 1.8-3.5). Compared with patients with no ischemia (event rate, 2.3 per 100 patient-years), patients with mental stress-induced ischemia alone had a significantly increased risk (event rate, 4.8 per 100 patient-years; HR, 2.0; 95% CI, 1.1-3.7) as did patients with both mental stress ischemia and conventional stress ischemia (event rate, 8.1 per 100 patient-years; HR, 3.8; 95% CI, 2.6-5.6). Patients with conventional stress ischemia alone did not have a significantly increased risk (event rate, 3.1 per 100 patient-years; HR, 1.4; 95% CI, 0.9-2.1). Patients with both mental stress ischemia and conventional stress ischemia had an elevated risk compared with patients with conventional stress ischemia alone (HR, 2.7; 95% CI, 1.7-4.3). The secondary end point occurred in 319 participants. The event rate was 12.6 per 100 patient-years for patients with and 5.6 per 100 patient-years for patients without mental stress-induced ischemia (adjusted HR, 2.0; 95% CI, 1.5-2.5). Conclusions and Relevance: Among patients with stable coronary heart disease, the presence of mental stress-induced ischemia, compared with no mental stress-induced ischemia, was significantly associated with an increased risk of cardiovascular death or nonfatal myocardial infarction. Although these findings may provide insights into mechanisms of myocardial ischemia, further research is needed to assess whether testing for mental stress-induced ischemia has clinical value.

Circulating Progenitor Cells and Racial Differences.

RATIONALE: Blacks compared with whites have a greater risk of adverse cardiovascular outcomes. Impaired regenerative capacity, measured as lower levels of circulating progenitor cells (CPCs), is a novel determinant of adverse outcomes; however, little is known about racial differences in CPCs. OBJECTIVE: To investigate the number of CPCs, PC-mobilizing factors, PC mobilization during acute myocardial infarction and the predictive value of CPC counts in blacks compared with whites. METHODS AND RESULTS: CPCs were enumerated by flow cytometry as CD45med+ blood mononuclear cells expressing CD34+, CD133+, VEGF2R+, and CXCR4+ epitopes in 1747 subjects, mean age 58.4±13, 55% male, and 26% self-reported black. Patients presenting with acute myocardial infarction (n=91) were analyzed separately. Models were adjusted for relevant clinical variables. SDF-1α (stromal cell-derived factor-1α), VEGF (vascular endothelial growth factor), and MMP-9 (matrix metallopeptidase-9) levels were measured (n=561), and 623 patients were followed for median of 2.2 years for survival analysis. Blacks were younger, more often female, with a higher burden of cardiovascular risk, and lower CPC counts. Blacks had fewer CD34+ cells (-17.6%; [95% confidence interval (CI), -23.5% to -11.3%]; P<0.001), CD34+/CD133+ cells (-15.5%; [95% CI, -22.4% to -8.1%]; P<0.001), CD34+/CXCR4+ cells (-17.3%; [95% CI, -23.9% to -10.2%]; P<0.001), and CD34+/VEGF2R+ cells (-27.9%; [95% CI, -46.9% to -2.0%]; P=0.04) compared with whites. The association between lower CPC counts and black race was not affected by risk factors or cardiovascular disease. Results were validated in a separate cohort of 411 patients. Blacks with acute myocardial infarction had significantly fewer CPCs compared with whites ( P=0.02). Blacks had significantly lower plasma MMP-9 levels ( P<0.001) which attenuated the association between low CD34+ and black race by 19% (95% CI, 13%-33%). However, VEGF and SDF-1α levels were not significantly different between the races. Lower CD34+ counts were similarly predictive of mortality in blacks (hazard ratio, 2.83; [95% CI, 1.12-7.20]; P=0.03) and whites (hazard ratio, 1.79; [95% CI, 1.09-2.94]; P=0.02) without significant interaction. CONCLUSIONS: Black subjects have lower levels of CPCs compared with whites which is partially dependent on lower circulating MMP-9 levels. Impaired regenerative capacity is predictive of adverse outcomes in blacks and may partly account for their increased risk of cardiovascular events.

Progenitor Cells and Clinical Outcomes in Patients With Acute Coronary Syndromes.

RATIONALE: Circulating progenitor cells (CPCs) mobilize in response to ischemic injury, but their predictive value remains unknown in acute coronary syndrome (ACS). OBJECTIVE: We aimed to investigate the number of CPCs in ACS compared with those with stable coronary artery disease (CAD), relationship between bone marrow PCs and CPCs, and whether CPC counts predict mortality in patients with ACS. METHODS AND RESULTS: In 2028 patients, 346 had unstable angina, 183 had an acute myocardial infarction (AMI), and the remaining 1499 patients had stable CAD. Patients with ACS were followed for the primary end point of all-cause death. CPCs were enumerated by flow cytometry as mononuclear cells expressing a combination of CD34+, CD133+, vascular endothelial growth factor receptor 2+, or chemokine (C-X-C motif) receptor 4+. CPC counts were higher in subjects with AMI compared those with stable CAD even after adjustment for age, sex, race, body mass index, renal function, hypertension, diabetes mellitus, hyperlipidemia, and smoking; CD34+, CD34+/CD133+, CD34+/CXCR4+, and CD34+/VEGFR2+ CPC counts were 19%, 25%, 28%, and 142% higher in those with AMI, respectively, compared with stable CAD. There were strong correlations between the concentrations of CPCs and the PC counts in bone marrow aspirates in 20 patients with AMI. During a 2 (interquartile range, 1.31-2.86)-year follow-up period of 529 patients with ACS, 12.4% died. In Cox regression models adjusted for age, sex, body mass index, heart failure history, estimated glomerular filtration rate, and AMI, subjects with low CD34+ cell counts had a 2.46-fold (95% confidence interval, 1.18-5.13) increase in all-cause mortality, P=0.01. CD34+/CD133+ and CD34+/CXCR4+, but not CD34+/VEGFR2+ PC counts, had similar associations with mortality. Results were validated in a separate cohort of 238 patients with ACS. CONCLUSIONS: CPC levels are significantly higher in patients after an AMI compared with those with stable CAD and reflect bone marrow PC content. Among patients with ACS, a lower number of hematopoietic-enriched CPCs are associated with a higher mortality.

Mental Stress-Induced-Myocardial Ischemia in Young Patients With Recent Myocardial Infarction: Sex Differences and Mechanisms.

BACKGROUND: Mental stress-induced myocardial ischemia (MSIMI) is frequent in patients with coronary artery disease and is associated with worse prognosis. Young women with a previous myocardial infarction (MI), a group with unexplained higher mortality than men of comparable age, have shown elevated rates of MSIMI, but the mechanisms are unknown. METHODS: We studied 306 patients (150 women and 156 men) ≤61 years of age who were hospitalized for MI in the previous 8 months and 112 community controls (58 women and 54 men) frequency matched for sex and age to the patients with MI. Endothelium-dependent flow-mediated dilation and microvascular reactivity (reactive hyperemia index) were measured at rest and 30 minutes after mental stress. The digital vasomotor response to mental stress was assessed using peripheral arterial tonometry. Patients received 99mTc-sestamibi myocardial perfusion imaging at rest, with mental (speech task) and conventional (exercise/pharmacological) stress. RESULTS: The mean age of the sample was 50 years (range, 22-61). In the MI group but not among controls, women had a more adverse socioeconomic and psychosocial profile than men. There were no sex differences in cardiovascular risk factors, and among patients with MI, clinical severity tended to be lower in women. Women in both groups showed a higher peripheral arterial tonometry ratio during mental stress but a lower reactive hyperemia index after mental stress, indicating enhanced microvascular dysfunction after stress. There were no sex differences in flow-mediated dilation changes with mental stress. The rate of MSIMI was twice as high in women as in men (22% versus 11%, P=0.009), and ischemia with conventional stress was similarly elevated (31% versus 16%, P=0.002). Psychosocial and clinical risk factors did not explain sex differences in inducible ischemia. Although vascular responses to mental stress (peripheral arterial tonometry ratio and reactive hyperemia index) also did not explain sex differences in MSIMI, they were predictive of MSIMI in women only. CONCLUSIONS: Young women after MI have a 2-fold likelihood of developing MSIMI compared with men and a similar increase in conventional stress ischemia. Microvascular dysfunction and peripheral vasoconstriction with mental stress are implicated in MSIMI among women but not among men, perhaps reflecting women's proclivity toward ischemia because of microcirculatory abnormalities.

Telomere Shortening, Regenerative Capacity, and Cardiovascular Outcomes.

RATIONALE: Leukocyte telomere length (LTL) is a biological marker of aging, and shorter LTL is associated with adverse cardiovascular outcomes. Reduced regenerative capacity has been proposed as a mechanism. Bone marrow-derived circulating progenitor cells are involved in tissue repair and regeneration. OBJECTIVE: Main objective of this study was to examine the relationship between LTL and progenitor cells and their impact on adverse cardiovascular outcomes. METHODS AND RESULTS: We measured LTL by quantitative polymerase chain reaction in 566 outpatients (age: 63±9 years; 76% men) with coronary artery disease. Circulating progenitor cells were enumerated by flow cytometry. After adjustment for age, sex, race, body mass index, smoking status, and previous myocardial infarction, a shorter LTL was associated with a lower CD34+ cell count: for each 10% shorter LTL, CD34+ levels were 5.2% lower (P<0.001). After adjustment for the aforementioned factors, both short LTL (

Sex Differences in Hemodynamic and Microvascular Mechanisms of Myocardial Ischemia Induced by Mental Stress.

OBJECTIVE: To investigate sex-specific vascular mechanisms for mental stress-induced myocardial ischemia (MSIMI). APPROACH AND RESULTS: Baseline data from a prospective cohort study of 678 patients with coronary artery disease underwent myocardial perfusion imaging before and during a public speaking stressor. The rate-pressure product response was calculated as the difference between the maximum value during the speech minus the minimum value during rest. Peripheral vasoconstriction by peripheral arterial tonometry was calculated as the ratio of pulse wave amplitude during the speech over the resting baseline; ratios <1 indicate a vasoconstrictive response. MSIMI was defined as percent of left ventricle that was ischemic and as a dichotomous variable. Men (but not women) with MSIMI had a higher rate-pressure product response than those without MSIMI (6500 versus 4800 mm Hg bpm), whereas women (but not men) with MSIMI had a significantly lower peripheral arterial tonometry ratio than those without MSIMI (0.5 versus 0.8). In adjusted linear regression, each 1000-U increase in rate-pressure product response was associated with 0.32% (95% confidence interval, 0.22-0.42) increase in inducible ischemia among men, whereas each 0.10-U decrease in peripheral arterial tonometry ratio was associated with 0.23% (95% confidence interval, 0.11-0.35) increase in inducible myocardial ischemia among women. Results were independent of conventional stress-induced myocardial ischemia. CONCLUSIONS: Women and men have distinct cardiovascular reactivity mechanisms for MSIMI. For women, stress-induced peripheral vasoconstriction with mental stress, and not increased hemodynamic workload, is associated with MSIMI, whereas for men, it is the opposite. Future studies should examine these pathways on long-term outcomes.

Use of High-Sensitivity Cardiac Troponin for the Exclusion of Inducible Myocardial Ischemia: A Cohort Study.

Background: Many patients with coronary artery disease (CAD) are routinely referred for surveillance stress testing despite recommendations against it. Objective: To determine whether low levels of resting high-sensitivity cardiac troponin I (hs-cTnI) can identify persons without inducible myocardial ischemia. Design: Observational study. Setting: A university-affiliated hospital network. Patients: Persons with stable CAD: 589 in the derivation group and 118 in the validation cohort. Measurements: Presence of inducible myocardial ischemia was determined by myocardial perfusion imaging with technetium-99m single-photon emission computed tomography during either treadmill or pharmacologic stress testing. Resting plasma hs-cTnI was measured within 1 week of the stress test, and the negative predictive value (NPV) for inducible ischemia was calculated. The derivation cohort was followed for 3 years for incident cardiovascular death and myocardial infarction. Results: In the derivation cohort, 10 of 101 patients with an hs-cTnI level below 2.5 pg/mL had inducible myocardial ischemia (NPV, 90% [95% CI, 83% to 95%]) and 3 of 101 had inducible ischemia involving at least 10% of the myocardium (NPV, 97% [CI, 92% to 99%]). In the validation cohort, 4 of 32 patients with an hs-cTnI level below 2.5 pg/mL had inducible ischemia (NPV, 88% [CI, 71% to 96%]) and 2 of 32 had ischemia of 10% or greater (NPV, 94% [CI, 79% to 99%]). After a median follow-up of 3 years in the derivation cohort, no adverse events occurred in patients with an hs-cTnI level below 2.5 pg/mL, compared with 33 (7%) cardiovascular deaths or incident myocardial infarctions among those with an hs-cTnI level of 2.5 pg/mL or greater. Limitation: The data may not be applicable to a population without known CAD or to persons with unstable angina, and the modest sample sizes warrant further validation in a larger cohort. Conclusion: Very low hs-cTnI levels may be useful in excluding inducible myocardial ischemia in patients with stable CAD. Primary Funding Source: National Institutes of Health.

Inflammatory response to mental stress and mental stress induced myocardial ischemia.

BACKGROUND: Mental stress-induced myocardial ischemia (MSIMI) is associated with increased risk of adverse cardiovascular outcomes, yet the underlying mechanisms are not well understood. We measured the inflammatory response to acute laboratory mental stress in patients with coronary artery disease (CAD) and its association with MSIMI. We hypothesized that patients with MSIMI would have a higher inflammatory response to mental stress in comparison to those without ischemia. METHODS: Patients with stable CAD underwent 99mTc sestamibi myocardial perfusion imaging during mental stress testing using a public speaking stressor. MSIMI was determined as impaired myocardial perfusion using a 17-segment model. Inflammatory markers including interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), matrix metallopeptidase 9 (MMP-9) and high-sensitivity C reactive protein (hsCRP) were measured at rest and 90 min after mental stress. Results were validated in an independent sample of 228 post-myocardial infarction patients. RESULTS: Of 607 patients analyzed in this study, (mean age 63 ±â€¯9 years, 76% male), 99 (16.3%) developed MSIMI. Mental stress resulted in a significant increase in IL-6, MCP-1, and MMP-9 (all p <0.0001), but not hsCRP. However, the changes in these markers were similar in those with and without MSIMI. Neither resting levels of these biomarkers, nor their changes with mental stress were significantly associated with MSIMI. Results in the replication sample were similar. CONCLUSION: Mental stress is associated with acute increases in several inflammatory markers. However, neither the baseline inflammatory status nor the magnitude of the inflammatory response to mental stress over 90 min were significantly associated with MSIMI.

Effect of Angiotensin II Type I Receptor Blockade with Valsartan on Carotid Artery Atherosclerosis: A Double Blind Randomized Clinical Trial Comparing Valsartan and Placebo (EFFERVESCENT).

BACKGROUND: Progression of atherosclerosis is associated with a greater risk for adverse outcomes. Angiotensin II plays a key role in the pathogenesis and progression of atherosclerosis. We aimed to investigate the effects of angiotensin II type-1 receptor blockade with Valsartan on carotid wall atherosclerosis, with the hypothesis that Valsartan will reduce progression of atherosclerosis. METHODS: Subjects (n = 120) with carotid intima-media thickness >0.65 mm by ultrasound were randomized (2:1) in a double-blind manner to receive either Valsartan or placebo for 2 years. Bilateral T2-weighted black-blood carotid magnetic resonance imaging was performed at baseline, 12 and 24 months. Changes in the carotid bulb vessel wall area and wall thickness were primary endpoints. Secondary endpoints included changes in carotid plaque thickness, plasma levels of aminothiols, C-reactive protein, fibrinogen, and endothelium-dependent and -independent vascular function. RESULTS: Over 2 years, the carotid bulb vessel wall area decreased with Valsartan (-6.7, 95% CI [-11.6, -1.9] mm(2)) but not with placebo (3.4, 95% CI [-2.8, 9.6] mm(2)), P = .01 between groups. Similarly, mean wall thickness decreased with Valsartan (-0.18, 95% CI [-0.30, -0.06] mm), but not with placebo (0.08, 95% CI [-0.07, 0.23] mm), P = .009 between groups. Furthermore, plaque thickness decreased with Valsartan (-0.35, 95% CI [-0.63, -0.08] mm) but was unchanged with placebo (+0.28, 95% CI [-0.11, 0.69] mm), P = .01 between groups. These findings were unaffected by statin therapy or changes in blood pressure. Notably, there were significant improvements in the aminothiol cysteineglutathione disulfide, and trends to improvements in fibrinogen levels and endothelium-independent vascular function. CONCLUSIONS: In subjects with carotid wall thickening, angiotensin II type-1 receptor blockade was associated with regression in carotid atherosclerosis. Whether these effects translate into improved outcomes in subjects with subclinical atherosclerosis warrants investigation.

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.

N terminal pro-brain natriuretic peptide level and benefits of chronic total occlusion revascularization.

BACKGROUND: The management of revascularization of chronic total occlusions (CTOs) remains controversial. Whether specific patients gain survival benefit from CTO revascularization remains unknown. OBJECTIVES: We investigated whether (i) patients with CTO have higher N terminal pro-brain natriuretic peptide (NT pro-BNP) levels than patients without CTO, (ii) in patients with CTO, NT pro-BNP levels predict adverse events, and (iii) those with elevated levels benefit from revascularization. METHODS: In 392 patients with stable, significant coronary artery disease (CAD) and CTO undergoing coronary angiography, rates of all-cause mortality, cardiovascular death, and a composite (cardiovascular death, myocardial infarction and heart failure hospitalizations) were investigated. Unadjusted and adjusted Cox proportional and Fine and Gray sub-distribution hazard models were performed to determine the association between NT pro-BNP levels and incident event rates in patients with CTO. RESULTS: NT pro-BNP levels were higher in patients with, compared to those without CTO (median 230.0 vs. 177.7 pg/mL, p ≤0.001). Every doubling of NT pro-BNP level in patients with CTO was associated with a > 25% higher rate of adverse events. 111 (28.5%) patients underwent CTO revascularization. In patients with elevated NT pro-BNP levels (> 125 pg/mL), those who underwent CTO revascularization had substantially lower adverse event rates compared to patients without CTO revascularization (adjusted cardiovascular death hazard ratio 0.29, 95% confidence interval (0.09-0.88). However, in patients with low NT pro-BNP levels (≤ 125 pg/mL), event rates were similar in those with and without CTO revascularization. CONCLUSION: NT pro-BNP levels can help identify individuals who may benefit from CTO revascularization.

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.

Vitamin D Deficiency, Inflammation, and Diminished Endogenous Regenerative Capacity in Coronary Heart Disease.

Background: Vitamin D deficiency (VDD) is associated with coronary heart disease (CHD) and poor outcomes, but supplementation does not improve prognosis. VDD has been implicated in and may promote greater risk through inflammation and impaired progenitor cell function. Objectives: The authors examined VDD, high-sensitivity C-reactive protein (hsCRP), circulating progenitor cell (CPC) counts, and outcomes in patients with CHD. They hypothesized that the higher risk with VDD is mediated by inflammation and impaired regenerative capacity. Methods: A total of 5,452 individuals with CHD in the Emory Cardiovascular Biobank had measurement of 25-hydroxyvitamin D, subsets of whom had hsCRP measurements and CPCs estimated as CD34-expressing mononuclear cell counts. Findings were validated in an independent cohort. 25-hydroxyvitamin D <20 ng/mL was considered VDD. Cox and Fine-Gray models determined associations between marker levels and: 1) all-cause mortality; 2) cardiovascular mortality; and 3) major adverse cardiovascular events, a composite of adverse CHD outcomes. Results: VDD (43.6% of individuals) was associated with higher adjusted cardiovascular mortality (HR: 1.57, 95% CI: 1.09-2.28). There were significant interactions between VDD and hsCRP and CPC counts in predicting cardiovascular mortality. Individuals with both VDD and elevated hsCRP had the greatest risk (HR: 2.82, 95% CI: 2.16-3.67). Only individuals with both VDD and low CPC counts were at high risk (HR: 2.25, 95% CI: 1.46-3.46). These findings were reproduced in the validation cohort. Conclusions: VDD predicts adverse outcomes in CHD. Those with VDD, inflammation and/or diminished regenerative capacity are at a significantly greater risk of cardiovascular mortality. Whether targeted supplementation in these high-risk groups improves risk warrants further study.

Hemodynamic Reactivity to Mental Stress in Patients With Coronary Artery Disease.

Importance: The clinical significance of hemodynamic reactivity to mental stress in the population with coronary artery disease (CAD) is unclear. Objective: To investigate the association between hemodynamic reactivity to mental stress and the risk of adverse cardiovascular events in patients with stable CAD. Design, Setting, and Participants: This cohort study included individuals with stable CAD from 2 prospective studies from a university-based hospital network: the Mental Stress Ischemia Prognosis Study (MIPS) and the Myocardial Infarction and Mental Stress Study 2 (MIMS2). Participants were enrolled between June 2011 and March 2016 and followed up for a median of 6.0 (IQR, 5.6-6.0) years in MIPS and 4.6 (IQR, 3.8-5.3) years in MIMS2. Data were analyzed from December 1, 2022, to February 15, 2023. Exposures: The rate-pressure product (RPP) was calculated as the mean systolic blood pressure times the mean heart rate at rest. Rate-pressure product reactivity was calculated as the maximum RPP during a standardized mental stress test minus the RPP at rest. Main Outcomes and Measures: The primary outcome was a composite of cardiovascular death or nonfatal myocardial infarction. The secondary end point additionally included hospitalizations for heart failure. Results: From the total of 938 individuals from the pooled cohort (mean [SD] age, 60.2 [10.1] years; 611 [65.1%] men), 631 participated in MIPS and 307 in MIMS2. A total of 373 individuals (39.8%) were Black, 519 (55.3%) were White, and 46 (4.9%) were of unknown race or ethnicity. The RPP increased by a mean (SD) of 77.1% (23.1%) during mental stress (mean [SD] absolute change, 5651 [2878]). For every SD decrease in RPP reactivity with mental stress, the adjusted hazard ratios for the primary and secondary end points were 1.30 (95% CI, 1.04-1.72) and 1.30 (95% CI, 1.06-1.56), respectively, in MIPS and 1.41 (95% CI, 1.06-1.97) and 1.21 (95% CI, 1.02-1.60), respectively, in MIMS2. In the pooled sample, when RPP reactivity to mental stress was added to a model including traditional clinical risk characteristics, model discrimination for adverse events improved (increase in C statistic of 5% for the primary end point; P = .009). Conclusions and Relevance: In this cohort study of individuals with stable CAD, a blunted cardiovascular reactivity to mental stress was associated with adverse outcomes. Future studies are needed to assess the clinical utility of mental stress reactivity testing in this population.

High Sensitivity Troponin Level and Benefits of Chronic Total Occlusion Revascularization.

Background The survival benefit of revascularization of chronic total occlusion (CTO) of the coronary arteries remains a subject of controversy. We measured high sensitivity troponin-I (hsTn-I) levels as an estimate of myocardial ischemia in patients with stable coronary artery disease, with the hypothesis that (1) patients with CTO have higher levels of hsTn-I than patients without CTO, (2) hsTn-I levels will predict adverse cardiovascular events in patients with CTO, and (3) patients with elevated hsTn-I levels will have a survival benefit from CTO revascularization. Methods and Results In 428 patients with stable coronary artery disease and CTO undergoing coronary angiography, adverse event rates were investigated. Cox proportional hazards models and Fine and Gray subdistribution hazard models were performed to determine the association between hsTn-I level and incident event rates in patients with CTO. HsTn-I levels were higher in patients with compared with those without CTO (median 6.7 versus 5.6 ng/L, P=0.002). An elevated hsTn-I level was associated with higher adverse event rates (adjusted all-cause mortality hazard ratio, 1.19 [95% CI, 1.08-1.32]; P=0.030) for every doubling of hsTn-I level. CTO revascularization was performed in 28.3% of patients. In patients with a high (>median) hsTn-I level, CTO revascularization was associated with substantially lower all-cause mortality (adjusted hazard ratio, 0.26 [95% CI, 0.08-0.88]; P=0.030) compared with those who did not undergo revascularization. In patients with a low (

Aggregate Clinical and Biomarker-Based Model Predicts Adverse Outcomes in Patients With Coronary Artery Disease.

Despite guideline-based therapy, patients with coronary artery disease (CAD) are at widely variable risk for cardiovascular events. This variability demands a more individualized risk assessment. Herein, we evaluate the prognostic value of 6 biomarkers: high-sensitivity C-reactive protein, heat shock protein-70, fibrin degradation products, soluble urokinase plasminogen activator receptor, high-sensitivity troponin I, and B-type natriuretic peptide. We then develop a multi-biomarker-based cardiovascular event prediction model for patients with stable CAD. In total, 3,115 subjects with stable CAD who underwent cardiac catheterization at Emory (mean age 62.8 years, 17% Black, 35% female, 57% obstructive CAD, 31% diabetes mellitus) were randomized into a training cohort to identify biomarker cutoff values and a validation cohort for prediction assessment. Main outcomes included (1) all-cause death and (2) a composite of cardiovascular death and nonfatal myocardial infarction (MI) within 5 years. Elevation of each biomarker level was associated with higher event rates in the training cohort. A biomarker risk score was created using optimal cutoffs, ranging from 0 to 6 for each biomarker exceeding its cutoff. In the validation cohort, each unit increase in the biomarker risk score was independently associated with all-cause death (hazard ratio 1.62, 95% confidence interval [CI] 1.45 to 1.80) and cardiovascular death/MI (hazard ratio 1.52, 95% CI 1.35 to 1.71). A biomarker risk prediction model for cardiovascular death/MI improved the c-statistic (∆ 6.4%, 95% CI 3.9 to 8.8) and net reclassification index by 31.1% (95% CI 24 to 37), compared with clinical risk factors alone. Integrating multiple biomarkers with clinical variables refines cardiovascular risk assessment in patients with CAD.