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 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 (ß=-0.92, P=0.043 and ß=-1.64, P=0.019, respectively) that was confirmed in cohort 2 (ß=-1.25, P=0.020 and ß=-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.

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. METHODS AND RESULTS: 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.

Coronary artery disease potentiates response to dofetilide for rhythm control of atrial fibrillation.

BACKGROUND: Dofetilide, a class III antiarrhythmic, is one of the few alternatives to amiodarone in patients with atrial fibrillation (AF) and heart failure or coronary artery disease (CAD). While amiodarone has been extensively studied, little is known about predictors of response to dofetilide. We sought to identify clinical parameters associated with dofetilide success in a large cohort of patients with AF. METHODS/RESULTS: A total of 287 patients with AF started on dofetilide between 2001 and 2008 were included. Dofetilide was deemed "completely effective" if the patient remained on dofetilide at follow-up and had no recurrences of AF clinically or by electrocardiogram. Dofetilide efficacy was analyzed in relation to clinical variables relevant to AF and AF recurrence. After a follow-up of 10.2 ± 7.7 months, 54.7% of the patients remained on dofetilide and it was completely effective in 26.8%. The discontinuation rate during initial hospitalization was 13.3% from excessive QT prolongation and one patient with torsades de pointes (successfully treated). A history of CAD was the only univariate predictor of efficacy (odds ratio [OR] 2.27, 95% confidence interval [CI] 1.29-4.01, P < 0.05). CAD remained the only significant factor associated with efficacy of dofetilide in a multivariate regression model (OR 2.01, 95% CI 1.11-3.70, P < 0.05, n = 270). The overall efficacy of dofetilide in patients with CAD was 41.1%, compared to 23.5% in those without CAD (P < 0.05). CONCLUSIONS: In this large cohort of patients with AF, underlying coronary disease was significantly associated with dofetilide success. This finding may have utility for clinical decisions regarding initiation of dofetilide.

Alcohol and the heart: an ounce of prevention.

OPINION STATEMENT: Moderate 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.

Cannabis Use Is an Independent Predictor for Acute Myocardial Infarction Related Hospitalization in Younger Population.

PURPOSE: This study aimed to evaluate the risk of various substances in young acute myocardial infarction (AMI) inpatients and analyze patient demographics and hospital outcomes for significant substance use risk factors. METHODS: We conducted a retrospective analysis of the Nationwide Inpatient Sample data (2010-2014). Patients (aged 15-22 years) with a primary diagnosis for AMI (N = 1,694) were compared with non-AMI (N = 9,465,255) inpatients for odds ratio (OR) of substance use by logistic regression model, adjusted for demographics, medical risk factors, and comorbid substance use. RESULTS: Tobacco (28.4%) and cannabis (14.9%) use were most prevalent in AMI inpatients. Cocaine (OR = 3.9), amphetamine (OR = 2.3), and cannabis (OR = 1.3) users were at higher risk of AMI hospitalizations. Higher proportion of cannabis users (14.7%) had major severity of illness at admission and higher mean total charge ($53,608) compared with that seen in cocaine and amphetamine users. Angioplasty was used more in cannabis users (19.4%) than others. The in-hospital mortalities were 2.7% and 2% in overall AMI cohort and cannabis users, respectively, and none in cocaine and amphetamine users. CONCLUSIONS: Our study demonstrates a higher prevalence and significant odds of AMI inpatients with cannabis use, along with the potential cost burdens because of severe morbidity and higher use of treatment modalities. Physicians need to familiarize themselves with rising use of cannabis and other substances in adolescent and younger population and the typical presentations of cannabis-induced myocardial infarction.

Factors Predicting Length of Stay in an Adolescent Psychiatric Unit, South Bronx, NY: A Short Report.

OBJECTIVE: Mental health disorders account for around 1.8 million inpatient community hospital stays in the U.S.A. Our study aims to highlight the factors impacting the length of stay at a community hospital in the U.S.A. METHODS: We reviewed 300 randomly selected charts to examine the factors impacting the length of stay in an adolescent inpatient psychiatric unit in 2011 and 2015. All data were analyzed in SPSS v. 20 with multiple regression analysis. RESULTS: Longer length of stay among adolescents was associated with multiple psychiatric diagnoses, co-occurring medical comorbidities, not living with biological parents, history of mental illness, legal problems, substance use in the family, seclusion, restraints during current admission, and schizophrenia. CONCLUSION: Longer length of stay among adolescents in a psychiatric inpatient unit was associated with severity of psychopathology, hospital parameters and family stability.

OBJECTIF: Les troubles de santé mentale représentent environ 1,8 million d'hospitalisations en hôpital communautaire aux États-Unis. Notre étude vise à mettre en évidence les facteurs influant sur la durée de séjour à un hôpital communautaire aux États-Unis. MÉTHODES: Nous avons étudié 300 dossiers choisis au hasard pour examiner les facteurs influant sur la durée de séjour dans une unité de psychiatrie pour adolescents hospitalisés en 2011 et 2015. Toutes les données ont été analysées au moyen du programme SPSS contre 20 par une analyse de régression multiple. RÉSULTATS: Une durée de séjour plus longue chez les adolescents était associée à de multiples diagnostics psychiatriques, à des comorbidité médicales co-occurrentes, au fait de ne pas habiter avec les parents biologiques, aux antécédents de maladie mentale, aux problèmes avec la justice, à l'utilisation de substances dans la famille, à l'isolement, à la contention durant l'hospitalisation en cours, et à la schizophrénie. CONCLUSION: Une durée de séjour plus longue chez les adolescents hospitalisés dans une unité de psychiatrie était associée à la gravité de la psychopathologie, aux paramètres de l'hôpital et à la stabilité familiale.

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.

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 (ß=9.53; P<0.001), Ln glutathione (ß=-5.4; P=0.002), and Eh glutathione (ß=0.21; P=0.001). A multivariate linear regression model adjusting for all confounding variables demonstrated that Ln cystine (ß=6.56; P=0.007), mitral regurgitation (ß=4.52; P<0.001), statin use (ß=-3.39; P=0.03), left ventricular ejection fraction (ß=-0.26; P=0.003), and age (ß=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 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. 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<0.0001) and its severity (P<0.0001). A plasma suPAR level ≥3.5 ng/mL (cutoff by Youden's 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.

Aggregate risk score based on markers of inflammation, cell stress, and coagulation is an independent predictor of adverse cardiovascular outcomes.

OBJECTIVES: This study sought to determine an aggregate, pathway-specific risk score for enhanced prediction of death and myocardial infarction (MI). BACKGROUND: Activation of inflammatory, coagulation, and cellular stress pathways contribute to atherosclerotic plaque rupture. We hypothesized that an aggregate risk score comprised of biomarkers involved in these different pathways-high-sensitivity C-reactive protein (CRP), fibrin degradation products (FDP), and heat shock protein 70 (HSP70) levels-would be a powerful predictor of death and MI. METHODS: Serum levels of CRP, FDP, and HSP70 were measured in 3,415 consecutive patients with suspected or confirmed coronary artery disease (CAD) undergoing cardiac catheterization. Survival analyses were performed with models adjusted for established risk factors. RESULTS: Median follow-up was 2.3 years. Hazard ratios (HRs) for all-cause death and MI based on cutpoints were as follows: CRP ≥3.0 mg/l, HR: 1.61; HSP70 >0.625 ng/ml, HR; 2.26; and FDP ≥1.0 µg/ml, HR: 1.62 (p < 0.0001 for all). An aggregate biomarker score between 0 and 3 was calculated based on these cutpoints. Compared with the group with a 0 score, HRs for all-cause death and MI were 1.83, 3.46, and 4.99 for those with scores of 1, 2, and 3, respectively (p for each: <0.001). Annual event rates were 16.3% for the 4.2% of patients with a score of 3 compared with 2.4% in 36.4% of patients with a score of 0. The C statistic and net reclassification improved (p < 0.0001) with the addition of the biomarker score. CONCLUSIONS: An aggregate score based on serum levels of CRP, FDP, and HSP70 is a predictor of future risk of death and MI in patients with suspected or known CAD.