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Cardiovascular disease remains the leading cause of mortality in the USA and globally. Acute coronary syndromes (ACS) occur as a result of vulnerable atherosclerotic plaque rupture that triggers a cascade of reactions leading to platelet aggregation, thrombus formation and activation of the coagulation pathway at the site of coronary occlusion.1 Early recognition of these plaques may improve outcomes. Biomarkers reflecting various pathways of atherogenesis, including inflammation, cell stress and coagulation, have been shown to add significant risk discrimination for incident cardiovascular events.2,3 Only plasma glutathione, however, has been associated with intravascular imaging characteristics of “rupture-prone” plaques.4 Fibrin and fibrinogen degradation products (FDP) are byproducts of thrombin breakdown, and their increased circulating levels may reflect subclinical vascular thrombosis.5 Serum FDP levels are associated with coronary artery disease (CAD) incidence and adverse outcomes.2,6–8 Intravascular ultrasound (IVUS) allows direct, real-time visualization of the coronary lumen and has well-recognized clinical applications in defining the distribution and morphology of coronary plaques. Virtual histology-IVUS (VH-IVUS), with its ability to differentiate plaque tissue types based on radiofrequency signals, has become a useful technique for precise characterization of plaque composition and assessment of coronary plaque vulnerability.9 We hypothesized that elevated FDP levels will be associated with VH-IVUS features of plaque vulnerability.

Background : Soluble urokinase-type plasminogen activator receptor (suPAR) is a novel biomarker released from leukocytes and endothelial cells that has been associated with atherosclerotic cardiovascular disease. We hypothesized that plasma suPAR level is an independent predictor of coronary microvascular function. Methods : Coronary blood flow velocity and plasma suPAR levels were evaluated in patients with non-obstructive coronary artery disease. Coronary flow reserve (CFR) was calculated as the ratio of hyperemic to basal average peak blood flow velocity and coronary microvascular dysfunction was defined as CFR ≤ 2.0 in the setting of a fractional flow reserve value of ≥0.75. Plasma suPAR levels were measured using ELISA technique. The association between suPAR and CFR was investigated using univariate and multivariate regression analyses. Results : In 66 patients, 47% were men, 26% had diabetes, 68% had hypertension and 76% had dyslipidemia. Mean age was 55 ± 12 years and median suPAR level 2.82 (2.08–3.40) ng/mL. Plasma suPAR levels correlated with age (r = 0.31, p = 0.01), body mass index (r = 0.25, p = 0.04) and high-sensitivity C-reactive protein (hs-CRP) (r = 0.33, p = 0.009). While median suPAR level was not significantly different in patients with different cardiovascular risk factors, patients on statin therapy had significantly higher suPAR level (p = 0.03). SuPAR correlated negatively with CFR and, after multivariate adjustment for established cardiovascular risk factors, medications profiles and hs-CRP, suPAR remained an independent predictor of CFR (B = −0.30, p = 0.04), indicating an independent association between suPAR level and coronary microvascular function. Conclusions : In this cross-sectional study, plasma suPAR level was an independent predictor of coronary microvascular function. Larger prospective clinical trials are warranted to investigate the prognostic value of this novel biomarker and the role of immune dysregulation in coronary microvascular disease.

Rationale: Low circulating progenitor cell numbers and activity may reflect impaired intrinsic regenerative/reparative potential, but it remains uncertain whether this translates into a worse prognosis. Objectives: To investigate whether low numbers of progenitor cells associate with a greater risk of mortality in a population at high cardiovascular risk. Methods and Results: Patients undergoing coronary angiography were recruited into 2 cohorts (1, n=502 and 2, n=403) over separate time periods. Progenitor cells were enumerated by flow cytometry as CD45 med+ blood mononuclear cells expressing CD34, with additional quantification of subsets coexpressing CD133, vascular endothelial growth factor receptor 2, and chemokine (C-X-C motif) receptor 4. Coefficient of variation for CD34 cells was 2.9% and 4.8%, 21.6% and 6.5% for the respective subsets. Each cohort was followed for a mean of 2.7 and 1.2 years, respectively, for the primary end point of all-cause death. There was an inverse association between CD34 + and CD34 + /CD133 + cell counts and risk of death in cohort 1 (β=−0.92, P =0.043 and β=−1.64, P =0.019, respectively) that was confirmed in cohort 2 (β=−1.25, P =0.020 and β=−1.81, P =0.015, respectively). Covariate-adjusted hazard ratios in the pooled cohort (n=905) were 3.54 (1.67–7.50) and 2.46 (1.18–5.13), respectively. CD34 + /CD133 + cell counts improved risk prediction metrics beyond standard risk factors. Conclusions: Reduced circulating progenitor cell counts, identified primarily as CD34 + mononuclear cells or its subset expressing CD133, are associated with risk of death in individuals with coronary artery disease, suggesting that impaired endogenous regenerative capacity is associated with increased mortality. These findings have implications for biological understanding, risk prediction, and cell selection for cell-based therapies.

Objective : Stromal derived factor-1α/CXCL12 is a chemoattractant responsible for homing of progenitor cells to ischemic tissues. We aimed to investigate the association of plasma CXCL12 with long-term cardiovascular outcomes in patients with coronary artery disease (CAD). Methods : 785 patients aged: 63 ± 12 undergoing coronary angiography were independently enrolled into discovery ( N = 186) and replication ( N = 599) cohorts. Baseline levels of plasma CXCL12 were measured using Quantikine CXCL12 ELISA assay (R&D systems). Patients were followed for cardiovascular death and/or myocardial infarction (MI) for a mean of 2.6 yrs. Cox proportional hazard was used to determine independent predictors of cardiovascular death/MI. Results : The incidence of cardiovascular death/MI was 13% ( N = 99). High CXCL12 level based on best discriminatory threshold derived from the ROC analysis predicted risk of cardiovascular death/MI (HR = 4.81, p = 1 × 10 −6 ) independent of traditional risk factors in the pooled cohort. Addition of CXCL12 to a baseline model was associated with a significant improvement in c-statistic (AUC: 0.67–0.73, p = 0.03). Addition of CXCL12 was associated with correct risk reclassification of 40% of events and 10.5% of non-events. Similarly for the outcome of cardiovascular death, the addition of the CXCL12 to the baseline model was associated with correct reclassification of 20.7% of events and 9% of non-events. These results were replicated in two independent cohorts. Conclusion : Plasma CXCL12 level is a strong independent predictor of adverse cardiovascular outcomes in patients with CAD and improves risk reclassification.

Coronary heart disease (CHD) is characterized by abnormal intercellular communication and circulating microRNAs (miRNAs) are likely involved in this process. Here, we show that CHD was associated with changes in the transport of circulating miRNA, particularly decreased miRNA enrichment in microparticles (MPs). Additionally, MPs from CHD patients were less efficient at transferring miRNA to cultured HUVECs, which correlated with their diminished capacity to bind developmental endothelial locus-1 (Del-1). In summary, CHD was associated with distinct changes in circulating miRNA transport and these changes may contribute to the abnormal intercellular communication that underlies CHD initiation and progression.

Background— Inflammation, coagulation, and cell stress contribute to atherosclerosis and its adverse events. A biomarker risk score (BRS) based on the circulating levels of biomarkers C-reactive protein, fibrin degradation products, and heat shock protein-70 representing these 3 pathways was a strong predictor of future outcomes. We investigated whether soluble urokinase plasminogen activator receptor (suPAR), a marker of immune activation, is predictive of outcomes independent of the aforementioned markers and whether its addition to a 3-BRS improves risk reclassification. Methods and Results— C-reactive protein, fibrin degradation product, heat shock protein-70, and suPAR were measured in 3278 patients undergoing coronary angiography. The BRS was calculated by counting the number of biomarkers above a cutoff determined using the Youden’s index. Survival analyses were performed using models adjusted for traditional risk factors. A high suPAR level ≥3.5 ng/mL was associated with all-cause death and myocardial infarction (hazard ratio, 1.83; 95% confidence interval, 1.43–2.35) after adjustment for risk factors, C-reactive protein, fibrin degradation product, and heat shock protein-70. Addition of suPAR to the 3-BRS significantly improved the C statistic, integrated discrimination improvement, and net reclassification index for the primary outcome. A BRS of 1, 2, 3, or 4 was associated with a 1.81-, 2.59-, 6.17-, and 8.80-fold increase, respectively, in the risk of death and myocardial infarction. The 4-BRS was also associated with severity of coronary artery disease and composite end points. Conclusions— SuPAR is independently predictive of adverse outcomes, and its addition to a 3-BRS comprising C-reactive protein, fibrin degradation product, and heat shock protein-70 improved risk reclassification. The clinical utility of using a 4-BRS for risk prediction and management of patients with coronary artery disease warrants further study.

Introduction Soluble urokinase plasminogen activator receptor (suPAR) is an emerging inflammatory and immune biomarker. Whether suPAR level predicts the presence and the severity of coronary artery disease (CAD), and of incident death and myocardial infarction (MI) in subjects with suspected CAD, is unknown. Methods and Results We measured plasma suPAR levels in 3367 subjects (67% with CAD) recruited in the Emory Cardiovascular Biobank and followed them for adverse cardiovascular (CV) outcomes of death and MI over a mean 2.1±1.1 years. Presence of angiographic CAD (≥50% stenosis in ≥1 coronary artery) and its severity were quantitated using the Gensini score. Cox's proportional hazard survival and discrimination analyses were performed with models adjusted for established CV risk factors and C‐reactive protein levels. Elevated suPAR levels were independently associated with the presence of CAD ( P P P P P P =0.008) with the addition of suPAR. Conclusion Elevated levels of plasma suPAR are associated with the presence and severity of CAD and are independent predictors of death and MI in patients with suspected or known CAD.

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.

Background: Elevated pulmonary artery systolic pressure (PASP) is associated with a worse outcome in heart failure (HF), but the prognostic role of PASP in patients with coronary artery disease (CAD) remains unknown. Methods: 863 patients with known or suspected CAD (age: 64±13 years, 62% male) enrolled in the Emory Cardiovascular Biobank were followed for a median 455 days for all-cause death. Transthoracic echocardiographic parameters included measurement of left ventricular ejection fraction (LVEF, range: 5-80%) and diastolic function parameters. Youden’s index from the receiver operating curve analysis was used to determine the best discriminatory cutoff for PASP (cutoff=43 mmHg). Cox regression was performed to determine independent predictors of mortality. Results: 88 (10%) subjects died during follow-up. PASP correlated with left ventricular ejection fraction (LVEF, N=644, r=-0.20, p50% and no history of HF (HR: 4.7, p=0.004). In separate models, this association was also independent of LAs and E/A. Conclusion: High PASP >43 mmHg is an independent predictor of mortality in patients with CAD even in those with preserved LVEF without HF. Whether high PASP predicts future development of HF and hospitalization for HF exacerbation needs to be investigated.

Oxidative stress contributes to the development of pulmonary hypertension in experimental models, but this association in humans is unknown. We investigated the relationship between pulmonary artery systolic pressure measured by echocardiography and plasma aminothiol oxidative stress markers, with the hypothesis that oxidative stress will be higher in those with pulmonary hypertension. A group of 347 patients aged 65±12 years from the Emory Cardiovascular Biobank underwent echocardiographic assessment of left ventricular ejection fraction and pulmonary artery systolic pressure. Plasma aminothiols, cysteine, its oxidized form, cystine, glutathione, and its oxidized disulphide were measured and the redox potentials (E h ) of cysteine/cystine and glutathione/oxidized glutathione couples were calculated. Non-normally distributed variables were log transformed (L n ). Univariate predictors of pulmonary artery systolic pressure included age ( P P =0.002), mitral regurgitation ( P P P P =0.03), plasma L n cystine (β=9.53; P n glutathione (β=−5.4; P =0.002), and E h glutathione (β=0.21; P =0.001). A multivariate linear regression model adjusting for all confounding variables demonstrated that L n cystine (β=6.56; P =0.007), mitral regurgitation (β=4.52; P P =0.03), left ventricular ejection fraction (β=−0.26; P =0.003), and age (β=0.17; P =0.003) were independent predictors of pulmonary artery systolic pressure. For each 1% increase in plasma cystine, pulmonary artery systolic pressure increased by 16%. This association persisted in the subgroup with preserved left ventricular ejection fraction (≥50%) and no significant mitral regurgitation. Whether treatment of oxidative stress will improve pulmonary hypertension requires further study.

Soluble urokinase plasminogen activator receptor (suPAR) is a biomarker of systemic inflammation. Recent studies have associated suPAR with presence and severity of coronary artery disease (CAD). However, the prognostic implication of suPAR in patients with left ventricular systolic dysfunction (

Activation of diverse pathophysiologic processes that include thrombotic, inflammatory, and immune pathways contribute to plaque rupture and adverse outcomes in CAD. We hypothesized that an aggregate biomarker risk score comprised of C-reactive protein (CRP), fibrin degradation products (FDP)

Recent advances in gene expression analysis have led to discoveries of signatures that are associated with presence and severity of coronary artery disease (CAD) and the risk of future outcomes in non-diabetics with CAD. We sought to identify signatures associated with acute myocardial infarction (

Asrac Caeor: 2. Chroc CAD/Sale Ischemc Hear Dsease: Clcalreseao Numer: 120-398Auhors: Nicholas A. Mantini, Danny Eapen, Frank Corrigan, Suliman Alradawi, Pankaj Manocha, Riyaz Patel, Muhammad Hammadah, Mohammad Tarek Kabbany, Ravi Nanjundappa, Rostam Zafari, James C. Lee, Hatem Al Kassem, Revanth Yendamuri, Ying X. Liu, Naureen Farook, Aliy M. Ahmed, Mohammad S. Qadir, Laurence Sperling, Arshed Quyyumi, Emory University School of Medicine, Atlanta, GA, USAIntroduction: sruce sleep apea (SA) s assocae wh oxae sress, rs acors clu hpereso, a wh ar presece o coroar arer sease (CAD). Howeer, wheher SA corues o he seer o CAD a o uure aerse ees paes wh CAD remas uow. We hpohesze ha SA wll e assocae wh reaer seer o coroar aheroscleross a worse caroascular oucomes.Methods: I a case-corol su o 893 paes recrue o he Emor Carolo oa who uerwe coroar aoraph, 402 ha ocumee SA a 491 were ree o SA. Seer o CAD was ocumee us he Ges score. aes were ollowe-up or 2.5 ears or prospece occurrece o maor aerse caroascular ees eie as eah, mocaral arco (MI) or reascularzao. Mularae lear reresso a Cox proporoal hazar moels were perorme o eerme he assocaos o SA wh CAD seer a oucomes.Results: Aer mularae ausme or ae, eer, smo, slpema, aees, o mass ex (MI), mecao, MI/SA eraco a eeco raco, SA remae a epee precor o hher Ges coroar seer score (p=.00). resece o SA was assocae wh a 3.4 (CI 1.48-8.2, p=0.007) reaer hazar or uure aerse CVD oucomes. Us Cox proporoal moel, here was worsee sural or hose wh SA compare o hose whou (p=.044).Conclusions: I uals wh ow CAD or a hh rs or aheroscleross, presece o SA s assocae wh a reaer seer o CAD a s prece o worse caroascular oucomes.