Pankaj Manocha

Circulating CD34+ Progenitor Cells and Risk of Mortality in a Population with Coronary Artery 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 CD45med+ 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 (&bgr;=−0.92, P=0.043 and &bgr;=−1.64, P=0.019, respectively) that was confirmed in cohort 2 (&bgr;=−1.25, P=0.020 and &bgr;=−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.

Soluble Urokinase Plasminogen Activator Receptor Level Is an Independent Predictor of the Presence and Severity of Coronary Artery Disease and of Future Adverse Events

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. Coxs 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<0.0001) and its severity (P<0.0001). A plasma suPAR level ≥3.5 ng/mL (cutoff by Youdens index) predicted future risk of MI (hazard ratio [HR]=3.2; P<0.0001), cardiac death (HR=2.62; P<0.0001), and the combined endpoint of death and MI (HR=1.9; P<0.0001), even after adjustment of covariates. The C‐statistic for a model based on traditional risk factors was improved from 0.72 to 0.74 (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.

Coronary heart disease alters intercellular communication by modifying microparticle-mediated microRNA transport

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.

Oxidative Stress Is Associated With Increased Pulmonary Artery Systolic Pressure in Humans

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 (Eh) of cysteine/cystine and glutathione/oxidized glutathione couples were calculated. Non-normally distributed variables were log transformed (Ln). Univariate predictors of pulmonary artery systolic pressure included age (P<0.001), sex (P=0.002), mitral regurgitation (P<0.001), left ventricular ejection fraction (P<0.001), left atrial size (P<0.001), diabetes mellitus (P=0.03), plasma Ln cystine (&bgr;=9.53; P<0.001), Ln glutathione (&bgr;=−5.4; P=0.002), and Eh glutathione (&bgr;=0.21; P=0.001). A multivariate linear regression model adjusting for all confounding variables demonstrated that Ln cystine (&bgr;=6.56; P=0.007), mitral regurgitation (&bgr;=4.52; P<0.001), statin use (&bgr;=−3.39; P=0.03), left ventricular ejection fraction (&bgr;=−0.26; P=0.003), and age (&bgr;=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.

Pathway-Specific Aggregate Biomarker Risk Score Is Associated With Burden of Coronary Artery Disease and Predicts Near-Term Risk of Myocardial Infarction and Death

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.

Elevated Levels of Serum Fibrin and Fibrinogen Degradation Products Are Independent Predictors of Larger Coronary Plaques and Greater Plaque Necrotic Core

BACKGROUND Co-existence of vulnerable plaque and pro-thrombotic state may provoke acute coronary events. It was hypothesized that elevated serum levels of fibrin and fibrinogen degradation products (FDP) are associated with larger total plaque and necrotic core (NC) areas. METHODSANDRESULTS Seventy-five patients presenting with stable anginal symptoms (69%) or stabilized acute coronary syndrome (ACS; 31%), and found to have non-obstructive coronary artery disease (CAD) with a fractional flow reserve >0.8, were studied. Invasive virtual histology intravascular ultrasound (VH-IVUS) was performed in 68 LAD arteries, 6 circumflex arteries, and 1 right coronary artery. Serum FDP levels were measured using ELISA technique. Plaque volumetrics and composition were assessed in each VH-IVUS frame and averaged. The median age of patients was 56 (47-63) years; 52% were men and 23% had diabetes. The average length of coronary artery studied was 62 mm. After adjustment for systemic risk factors, medications, CRP levels and ACS, male gender (P<0.001) and serum FDP levels (P=0.02) were independent predictors of a larger NC area. Older age (P<0.001), male gender (P<0.0001) and increased serum FDP level (P=0.03) were associated with a larger plaque area. CONCLUSIONS In patients with CAD, a higher serum level of FDP is independently associated with larger plaques and greater plaque NC.

Alcohol and the Heart: An Ounce of Prevention

Opinion StatementModerate alcohol intake is beneficial to the heart and cardiovascular system. A J- or U-shaped response has been shown in the majority of studies examining alcohol’s effect on cardiovascular mortality and downstream cardio-metabolic effects, with heavy alcohol intake associated with worse outcomes. These effects apply to individuals with and without underlying coronary artery disease. However, care must be taken in defining “moderate” intake between the sexes. Males appear to have a wider therapeutic window and can afford 2 to 3 drinks per day whereas women should limit intake to 1 to 2 drinks per day (a “drink” being classified as 10 to 14 grams of alcohol). More than half of alcohol’s cardioprotective effects can be attributed to its effect on lipoproteins, specifically an increase in high-density lipoprotein. Interestingly, the risk of cardiovascular mortality in former heavy drinkers has been shown to ultimately approach the risk seen in lifelong abstainers.

A DISTINCT PERIPHERAL BLOOD GENE EXPRESSION PROFILE IS ASSOCIATED WITH ACUTE MYOCARDIAL INFARCTION AND PREDICTS RISK OF CARDIOVASCULAR DEATH

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 (

OBSTRUCTIVE SLEEP APNEA IS ASSOCIATED WITH INCREASED SEVERITY OF CORONARY ARTERY DISEASE AND WORSE CARDIOVASCULAR OUTCOMES

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.

SOLUBLE UROKINASE PLASMINOGEN ACTIVATOR RECEPTOR IS AN INDEPENDENT PREDICTOR OF CARDIOVASCULAR OUTCOMES IN PATIENTS WITH LEFT VENTRICULAR SYSTOLIC DYSFUNCTION

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 (