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Bone marrow-derived progenitor cells are mobilized into the peripheral blood after acute myocardial injury and in chronic ischemic heart disease. However, the mechanisms responsible for this mobilization are poorly understood. We examined the relationship between plasma levels of bioactive lipids and number of circulating progenitor cells (CPCs) in patients (N = 437) undergoing elective or emergent cardiac catheterization. Plasma levels of sphingosine-1 phosphate (S1P) and ceramide-1 phosphate (C1P) were quantified using mass spectrometry. CPCs were assessed using flow cytometry. S1P levels correlated with the numbers of CD34+, CD34+/CD133+, and CD34+/CXCR4+ CPCs even after adjustment for potential confounding factors. However, no significant correlation was observed between C1P levels and CPC count. Plasma levels of S1P correlated with the number of CPCs in patients with coronary artery disease, suggesting an important mechanistic role for S1P in stem cell mobilization. The therapeutic effects of adjunctive S1P therapy to mobilize endogenous stem cells need to be investigated.

Rationale: Peripheral arterial disease (PAD) is a clinical manifestation of extracoronary atherosclerosis. Despite sharing the same risk factors, only 20% to 30% of patients with coronary artery disease (CAD) develop PAD. Decline in the number of bone marrow–derived circulating progenitor cells (PCs) is thought to contribute to the pathogenesis of atherosclerosis. Whether specific changes in PCs differentiate patients with both PAD and CAD from those with CAD alone is unknown. Objective: Determine whether differences exist in PCs counts of CAD patients with and without known PAD. Methods and Results: 1497 patients (mean age: 65 years; 62% men) with known CAD were identified in the Emory Cardiovascular Biobank. Presence of PAD (n=308) was determined by history, review of medical records, or imaging and was classified as carotid (53%), lower extremity (41%), upper extremity (3%), and aortic disease (33%). Circulating PCs were enumerated by flow cytometry. Patients with CAD and PAD had significantly lower PC counts compared with those with only CAD. In multivariable analysis, a 50% decrease in cluster of differentiation 34 (CD34+) or CD34+/vascular endothelial growth factor receptor-2 (VEGFR2+) counts was associated with a 31% ( P =0.032) and 183% ( P =0.002) increase in the odds of having PAD, respectively. CD34+ and CD34+/VEGFR2+ counts significantly improved risk prediction metrics for prevalent PAD. Low CD34+/VEGFR2+ counts were associated with a 1.40-fold (95% confidence interval, 1.03–1.91) and a 1.64-fold (95% confidence interval, 1.07–2.50) increases in the risk of mortality and PAD-related events, respectively. Conclusions: PAD is associated with low CD34+ and CD34+/VEGFR2+ PC counts. Whether low PC counts are useful in screening for PAD needs to be investigated.

BackgroundRelatively high plasma levels of soluble urokinase-type plasminogen activator receptor (suPAR) have been associated with focal segmental glomerulosclerosis and poor clinical outcomes in patients with various conditions. It is unknown whether elevated suPAR levels in patients with normal kidney function are associated with future decline in the estimated glomerular filtration rate (eGFR) and with incident chronic kidney disease. MethodsWe measured plasma suPAR levels in 3683 persons enrolled in the Emory Cardiovascular Biobank (mean age, 63 years; 65% men; median suPAR level, 3040 pg per milliliter) and determined renal function at enrollment and at subsequent visits in 2292 persons. The relationship between suPAR levels and the eGFR at baseline, the change in the eGFR over time, and the development of chronic kidney disease (eGFR

Background Being unmarried is associated with decreased survival in the general population. Whether married, divorced, separated, widowed, or never‐married status affects outcomes in patients with cardiovascular disease has not been well characterized. Methods and Results A prospective cohort (inception period 2003–2015) of 6051 patients (mean age 63 years, 64% male, 23% black) undergoing cardiac catheterization for suspected or confirmed coronary artery disease was followed for a median of 3.7 years (interquartile range: 1.7–6.7 years). Marital status was stratified as married (n=4088) versus unmarried (n=1963), which included those who were never married (n=451), divorced or separated (n=842), or widowed (n=670). The relationship between marital status and primary outcome of cardiovascular death and myocardial infarction was examined using Cox regression models adjusted for clinical characteristics. There were 1085 (18%) deaths from all causes, 688 (11%) cardiovascular‐related deaths, and 272 (4.5%) incident myocardial infarction events. Compared with married participants, being unmarried was associated with higher risk of all‐cause mortality (hazard ratio [HR]: 1.24; 95% confidence interval [ CI ], 1.06–1.47), cardiovascular death ( HR : 1.45; 95% CI , 1.18–1.78), and cardiovascular death or myocardial infarction ( HR : 1.52; 95% CI, 1.27–1.83). Compared with married participants, the increase in cardiovascular death or myocardial infarction was similar for the participants who were divorced or separated (HR: 1.41; 95% CI , 1.10–1.81), widowed (HR: 1.71; 95% CI , 1.32–2.20), or never married (HR: 1.40; 95% CI , 0.97–2.03). The findings persisted after adjustment for medications and other socioeconomic factors. Conclusions Marital status is independently associated with cardiovascular outcomes in patients with or at high risk of cardiovascular disease, with higher mortality in the unmarried population. The mechanisms responsible for this increased risk require further study.

Depression is common in patients with coronary artery disease (CAD) and is associated with more frequent chest pain. It is however unclear whether this is due to differences in underlying CAD severity. We sought to determine [1] whether depressive symptoms are associated with chest pain independently of CAD severity, [2] whether improvement in depressive symptoms over time is associated with improvement in chest pain and [3] whether the impact of revascularization on chest pain differs between patients with and without depression.5158 patients (mean age 63±12years, 65% male, 20% African American) undergoing cardiac catheterization completed the Seattle Angina Questionnaire (SAQ) and Patient Health Questionnaire-8 (PHQ-8) to assess angina severity and screen for depression, respectively, both at baseline and between 6 and 24months of follow-up. We found significant correlations between PHQ-8 scores and angina frequency (SAQ-AF, r=-0.28), physical limitation (SAQ-PL, r=-0.32) and disease perception (SAQ-DS r=-0.37, all P0.001), which remained significant after adjustment for clinical characteristics, CAD severity, and anti-depressant use. Improvement in depressive symptoms at follow-up was associated with improvement in angina subscales (SAQ-AF β 1.34, P0.001), SAQ-PL β 1.85, P0.001), and SAQ-DS (β 2.12, P0.001), independently of CAD severity or revascularization. Patients with depression who underwent revascularization had less improvement in chest pain frequency than those without depressive symptoms.Depression is associated with angina, independently of CAD severity. Patients with depression may not derive as adequate symptomatic benefit from revascularization as those without. Whether treatment of underlying depression improves chest pain needs to be further studied.

Extracellular miRNAs are detectable in biofluids and represent a novel class of disease biomarker. Although many studies have utilized archived plasma for miRNA biomarker discovery, the effects of processing and storage have not been rigorously studied. Previous reports have suggested plasma samples are commonly contaminated by platelets, significantly confounding the measurement of extracellular miRNA, which was thought to be easily addressed by additional post-thaw plasma processing. In a case-control study of archived plasma, we noted a significant correlation between miRNA levels and platelet counts despite post-thaw processing. We thus examined the effects of a single freeze/thaw cycle on microparticles (MPs) and miRNA levels, and show that a single freeze/thaw cycle of plasma dramatically increases the number of platelet-derived MPs, contaminates the extracellular miRNA pool, and profoundly affects the levels of miRNAs detected. The measurement of extracellular miRNAs in archived samples is critically dependent on the removal of residual platelets prior to freezing plasma samples. Many previous clinical studies of extracellular miRNA in archived plasma should be interpreted with caution and future studies should avoid the effects of platelet contamination.

Objective Exercise-induced cardiac dysfunction and corollary biomarker release have been documented following long-distance running events. To what degree these processes occur during shorter distance running events is unknown. Methods 72 healthy recreational runners (54% male/46% female) recruited by age (group 1 (18–20 years old, N=19); group 2 (45–50 years old, N=27); group 3 (70–75 years old, N=26)) were studied with echocardiography and biochemical profiling during participation in a 10 km running race. Results Despite age-dependent baseline differences in ventricular size and diastolic tissue velocities, there were no significant within group or across group decrements in ventricular systolic or diastolic function following race completion. Postrace increases in cardiac troponin-I (cTnI), B-type natriuretic peptide (BNP) and high-sensitivity C-reactive protein (hs-CRP) were common and demonstrated distinct age dependent profiles. Specifically, BNP increases were most pronounced among older runners (group 3Δ: 16±22 pg/mL, p=0.001), hs-CRP increased only among younger runners (group 1Δ: 1.5±2.7 mg/L, p=0.03) and cTnI increased in both younger (group 1Δ: 0.01±0.02 ng/mL, p=0.028) and older (group 3Δ: 0.01±0.01 ng/mL, p=0.007) runners, but not middle aged runners (group 2Δ: 0.00±0.00 ng/mL, p=0.57). Conclusions Moderate distance recreational running leads to distinct age-dependent biomarker release but is not associated with cardiac fatigue, a proposed stimulus for pathologic cardiac remodelling that has been observed following longer distance running events.

Age shifts have drastically changed the landscape of the U.S. population with nearly 1 in every 7 Americans being 65 years of age and older [(1)][1]. As the population ages, the impact on the health care system is expected to be dramatic, in particular as it relates to the care of patients with

miRNAs are short, noncoding RNAs that circulate in plasma within membrane-bound vesicles, such as microparticles (MPs), or bound to proteins or lipoproteins. Circulating miRNAs are putative biomarkers for a wide range of diseases, including cardiovascular disease. Our group and others have evidence to suggest MP-encapsulated miRNAs, rather than total plasma miRNAs, may harbor more specific and functionally relevant biomarkers. We tested the hypothesis that MP-encapsulated miRNA levels would differ between patients with mild or severe peripheral artery disease (PAD) and healthy controls matched for age, gender, and race. Banked plasma stored at -80°C was obtained for 5 healthy subjects, 6 patients with mild PAD (ABI 0.8-1.0), and 10 patients with severe PAD (ABI < 0.4). MPs were isolated using a standard differential centrifugation protocol and quantified by flow cytometry. Four miRNAs implicated in vascular disease (miR-126-3p, miR-126-5p, miR-21, and miR-222) were quantified with qRT-PCR. Relative expression for each miRNA (-2ΔCt) was calculated and divided the total number of MPs to determine miRNA expression per MP. There was a non-significant trend towards increased levels of MPs in patients with mild (19,462 MPs/μl ± 5,213) and severe PAD (21,688 MPs/μl ± 7,175) compared to healthy controls (7244 MPs/μl ± 919). MP levels of miR-126-5p were increased among healthy subjects compared to patients with mild and severe PAD (p = 0.003), while MP miR-126-3p levels were significantly lower in healthy subjects (p = 0.002). miR-21 and miR-222 did not differ significantly between groups. None of the four miRNAs distinguished mild versus severe PAD. In conclusion, our data suggests that MP-mediated transport of miR-126-5p and miR-126-3p is dysregulated in the setting of mild and severe vascular disease, and supports the concept that the plasma MP fraction may harbor disease-associated miRNA profiles.

Introduction: A family history (FH) of premature coronary artery disease (CAD) is an important prognostic risk factor. Emerging evidence suggests that CAD location as well as severity may be heritable. We sought to investigate the association between a FH of premature CAD with the location and severity of angiographically phenotyped CAD. Methods: 2854 patients undergoing coronary angiography were enrolled from the Emory Cardiovascular Biobank. A FH of CAD was defined as having any male or female relative with history of CAD at age ≤55 or ≤65 year old respectively. Coronary angiograms were phenotyped using a 17 segment AHA model. Proximal disease was defined as having ≥70% lesion in the left main or proximal portion of any of the three major epicardial arteries, while CAD severity was assessed by counting the number of vessels with ≥70% stenosis. Results: Among this population (mean age 63±12, male 67%, diabetes 33%), 21% reported a positive FH of premature CAD. After adjustment for age, gender, and traditional cardiovascular risk factors, those with a positive FH were more likely to have significant CAD than those without a positive FH (OR 1.3 (1.1-1.7)). They were 40% more likely to have single vessel (OR 1.4(1.1-1.7)) and up to 80% more likely to have multi-vessel disease (OR 1.8 (1.4-2.4)). In addition, they were also much more likely to have left main (OR 1.9 (1.3-2.8)) and proximal vessel involvement (OR 1.5 (1.2 - 1.9)), but not distal vessel stenosis (OR 1.1 (0.9-1.4)). Conclusions: A FH of CAD is associated with a greater likelihood of multi-vessel and proximal anatomical disease. Whether site specific disease is genetically mediated remains to be explored.

High-sensitivity Troponin-I (hs-TnI) as a marker of myocardial injury is predictive of adverse outcomes in patients with coronary artery disease (CAD). Whether the relationship between hs-TnI and outcomes is dependent on underlying CAD severity is unknown. 2826 patients without AMI (mean age 62, 64

Leucocyte telomere length (LTL) is a biological marker of aging which has been associated with decreased survival. Bone marrow-derived circulating progenitor cells (CPC) are involved in vascular repair and regeneration, and reduced CPC counts are associated with poor outcomes. We sought to determine

Participation in ultra-endurance exercise is associated with transient cardiac dysfunction, or cardiac fatigue. The effects of aging and participation in a moderate distance running race on changes in cardiac function have not been studied. 73 healthy runners spanning a wide age spectrum [(Group 1

Background: Three-dimensional design simulations of coronary metallic stents utilizing mathematical and computational algorithms have emerged as important tools for understanding biomechanical stent properties, predicting the interaction of the implanted platform with the adjacent tissue, and informing stent design enhancements. Herein, we demonstrate the hemodynamic implications following virtual implantation of bioresorbable scaffolds using finite element methods and advanced computational fluid dynamics (CFD) simulations to visualize the device-flow interaction immediately after implantation and following scaffold resorption over time. Methods and Results: CFD simulations with time averaged wall shear stress (WSS) quantification following virtual bioresorbable scaffold deployment in idealized straight and curved geometries were performed. WSS was calculated at the inflow, endoluminal surface (top surface of the strut), and outflow of each strut surface post-procedure (stage I) and at a time point when 33% of scaffold resorption has occurred (stage II). The average WSS at stage I over the inflow and outflow surfaces was 3.2 and 3.1 dynes/cm2 respectively and 87.5 dynes/cm2 over endoluminal strut surface in the straight vessel. From stage I to stage II, WSS increased by 100% and 142% over the inflow and outflow surfaces, respectively, and decreased by 27% over the endoluminal strut surface. In a curved vessel, WSS change became more evident in the inner curvature with an increase of 63% over the inflow and 66% over the outflow strut surfaces. Similar analysis at the proximal and distal edges demonstrated a large increase of 486% at the lateral outflow surface of the proximal scaffold edge. Conclusions: The implementation of CFD simulations over virtually deployed bioresorbable scaffolds demonstrates the transient nature of device/flow interactions as the bioresorption process progresses over time. Such hemodynamic device modeling is expected to guide future bioresorbable scaffold design.