Background-—Young women with coronary artery disease (CAD), a group with high psychosocial burden, were previously shown to have higher levels of interleukin-6 (IL-6) compared with men of similar age. We sought to examine IL-6 response to acute stress in CAD patients across sex and age, and contrast results to healthy controls and other biomarkers known to increase with mental stress (monocyte chemoattractant protein-1 and matrix metallopeptidase-9) and known limited stress-reactivity (high-sensitivity C-reactive protein). Methods and Results-—Inflammatory biomarkers were measured at rest and 90 minutes after mental stress (speech task) among 819 patients with CAD and 89 healthy controls. Repeated-measures models were used to investigate age (continuous) and sex differences across time, before and after adjusting for demographics, CAD risk factors, depressive symptoms, medication use, and CAD severity. Among patients with CAD, the mean age was 60 years (range, 25–79) and 31% were women. Younger women with CAD had significantly higher concentrations of IL-6 at rest, 90 minutes after mental stress, as well as a higher response to stress, compared with similarly aged men (P<0.05 for sex by age interactions). In contrast, IL-6 increased with age, and there were no sex differences in IL-6 levels or response to stress among controls. Inflammatory responses to stress for high-sensitivity C-reactive protein, monocyte chemoattractant protein-1, and matrix metallopeptidase-9 among CAD patients were similar in women and men. Conclusions-—IL-6 response to mental stress are higher in young women with CAD than men of similar age.
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Salim S. Hayek;
Yuri Klyachkin;
Ahmed Asfour;
Nima Ghasemzadeh;
Mosaab Awad;
Iraj Hesaroieh;
Hina Ahmed;
Brandon Gray;
Jonathan Kim;
Edmund Waller;
Arshed Quyyumi;
Ahmed K. Abdel-Latif
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 CD341, CD341/CD1331, and CD341/CXCR41CPCs 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.
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 2.6yrs. 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.
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 CD4+5 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.
BACKGROUND—: Free radical scavengers have failed to improve patient outcomes promoting the concept that clinically important oxidative stress (OS) may be mediated by alternative mechanisms. We sought to examine the association of emerging aminothiol markers of non-free radical mediated oxidative stress with clinical outcomes.
METHODS AND RESULTS—: Plasma levels of reduced (cysteine and glutathione) and oxidized (cystine and glutathione disulphide) aminothiols were quantified by high performance liquid chromatography in 1411 patients undergoing coronary angiography (mean age 63 years, male 66%). All patients were followed for a mean of 4.7±2.1 years for the primary outcome of all-cause death (n=247). Levels of cystine (oxidized) and glutathione (reduced) were associated with risk of death (p<0.001 both) before and after adjustment for covariates. High cystine and low glutathione levels (=+1 SD & <-1 SD respectively) were associated with higher mortality (adjusted HR 1.63 (95% CI 1.19-2.21; HR 2.19 (95% CI 1.50-3.19), respectively) compared to those outside these thresholds. Furthermore, the ratio of cystine/glutathione was also significantly associated with mortality (adjusted HR 1.92 (95% CI 1.39-2.64) and was independent of and additive to hs-CRP level. Similar associations were found for other outcomes of cardiovascular death and combined death and myocardial infarction.
CONCLUSIONS—: A high burden of OS, quantified by the plasma aminothiols, cystine, glutathione and their ratio is associated with mortality in patients with CAD, a finding that is independent of and additive to the inflammatory burden. Importantly, this data supports the emerging role of non-free radical biology in driving clinically important oxidative stress.
Objective: HIV is a cardiovascular disease (CVD) risk factor. However, CVD risk is often underestimated in HIV-infected women. C-reactive protein (CRP) may improve CVD prediction in this population. We examined the association of baseline plasma CRP with subclinical CVD in women with and without HIV.
Design: Retrospective cohort study.
Methods: A total of 572 HIV-infected and 211 HIV-uninfected women enrolled in the Women's Interagency HIV Study underwent serial high-resolution B-mode carotid artery ultrasonography between 2004 and 2013 to assess carotid intima-media thickness (CIMT) and focal carotid artery plaques. We used multivariable linear and logistic regression models to assess the association of baseline high (≥3 mg/l) high-sensitivity (hs) CRP with baseline CIMT and focal plaques, and used multivariable linear and Poisson regression models for the associations of high hsCRP with CIMT change and focal plaque progression. We stratified our analyses by HIV status.
Results: Median (interquartile range) hsCRP was 2.2 mg/l (0.8-5.3) in HIV-infected, and 3.2 mg/l (0.9-7.7) in HIV-uninfected, women (P = 0.005). There was no statistically significant association of hsCRP with baseline CIMT [adjusted mean difference -3.5 μm (95% confidence interval:-19.0 to 12.1)] or focal plaques [adjusted odds ratio: 1.31 (0.67-2.67)], and no statistically significant association of hsCRP with CIMT change [adjusted mean difference 11.4 μm (-2.3 to 25.1)]. However, hsCRP at least 3 mg/l was positively associated with focal plaque progression in HIV-uninfected [adjusted rate ratio: 5.97 (1.46-24.43)], but not in HIV-infected [adjusted rate ratio: 0.81 (0.47-1.42)] women (P = 0.042 for interaction).
Conclusion: In our cohort of women with similar CVD risk factors, higher baseline hsCRP is positively associated with carotid plaque progression in HIV-uninfected, but not HIV-infected, women, suggesting that subclinical CVD pathogenesis may be different HIV-infected women.
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Brian G. Kral;
Rasika A. Mathias;
Bhoom Suktitipat;
Ingo Ruczinski;
Dhananjay Vaidya;
Lisa R. Yanek;
Arshed Quyyumi;
Riyaz S. Patel;
Abarmard Zafari;
Laura Vaccarino;
Elizabeth R. Hauser;
William E. Kraus;
Lewis C. Becker;
Diane M. Becker
A 58kb region on chromosome 9p21.3 has consistently shown strong association with coronary artery disease (CAD) in multiple genome-wide association studies in populations of European and East Asian ancestry. In this study, we sought to further characterize the role of genetic variants in 9p21.3 in African American individuals. Apparently healthy African American siblings (n548) of patients with documented CAD < 60 years of age were genotyped and followed for incident CAD for up to 17 years. Tests of association for 86 single-nucleotide polymorphisms (SNPs) across the 9p21.3 region in a generalized estimating equation logistic framework under an additive model adjusting for traditional risk factors, family, follow-up time and population stratification were performed. A single SNP within the CDKN2B gene met stringent criteria for statistical significance, including permutation-based evaluations. This variant, rs3217989, was common (minor allele (G) frequency 0.242), conveyed protection against CAD (odds ratio (OR)0.19, 95 confidence interval (CI): 0.07 to 0.50, P0.0008) and was replicated in a combined analysis of two additional casecontrol studies of prevalent CADMI in African Americans (n990, P0.024, OR0.779, 95 CI: 0.626-0.968). This is the first report of a CAD association signal in a population of African ancestry with a common variant within the CDKN2B gene, independent from previous findings in European and East Asian ancestry populations. The findings demonstrate a significant protective effect against incident CAD in African American siblings of persons with premature CAD, with replication in a combination of two additional African American cohorts.
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Solveig Gretarsdottir;
Annette F. Baas;
Gudmar Thorleifsson;
Hilma Holm;
Martin den Heijer;
Jean-Paul P M de Vries;
Steef E. Kranendonk;
Clark J A M Zeebregts;
Steven M van Sterkenburg;
Robert H. Geelkerken;
Andre M. van Rij;
Michael K A Williams;
Albert P M Boll;
Jelena P. Kostic;
Adalbjorg Jonasdottir;
Aslaug Jonasdottir;
G. Bragi Walters;
Gisli Masson;
Patrick Sulem;
Jona Saemundsdottir;
Magali Mouy;
Kristinn P Magnusson;
Gerard Tromp;
James R. Elmore;
Natzi Sakalihasan;
Raymond Limet;
Allan Levey;
Arshed Quyyumi;
Laura Vaccarino;
Abarmard Zafari
We performed a genome-wide association study on 1,292 individuals with abdominal aortic aneurysms (AAAs) and 30,503 controls from Iceland and The Netherlands, with a follow-up of top markers in up to 3,267 individuals with AAAs and 7,451 controls. The A allele of rs7025486 on 9q33 was found to associate with AAA, with an odds ratio (OR) of 1.21 and P = 4.6 × 10 -10. In tests for association with other vascular diseases, we found that rs7025486[A] is associated with early onset myocardial infarction (OR = 1.18, P = 3.1 × 10-5), peripheral arterial disease (OR = 1.14, P = 3.9 × 10-5) and pulmonary embolism (OR = 1.20, P = 0.00030), but not with intracranial aneurysm or ischemic stroke. No association was observed between rs7025486[A] and common risk factors for arterial and venous diseasesĝ€"that is, smoking, lipid levels, obesity, type 2 diabetes and hypertension. Rs7025486 is located within DAB2IP, which encodes an inhibitor of cell growth and survival.
Background: Stress is an important contributor to myocardial ischemia and the progression of coronary artery disease (CAD), and women are more susceptible than men to these effects. Little is known, however, about the neural basis of these sex differences. Methods: We investigated sex differences in neural correlates of mental stress in a sample of 53 female and 112 male participants (N = 165) with CAD, with and without mental stress-induced myocardial ischemia (MSI), during exposure to mental arithmetic tasks and public speaking stress tasks using high-resolution positron emission tomography (HR-PET) and radiolabeled water imaging of the brain. Results: Women compared to men had significantly greater activation with stress in the right frontal (BA 9, 44), right parietal lobe (Area 3, 6, 40), right posterior cingulate gyrus (BA 31), bilateral cerebellum, and left temporal/fusiform gyrus (BA 37) and greater deactivation in bilateral anterior cingulate gyrus (BA 24, 32), bilateral medial frontal gyrus (BA 6, 8, 9, 10), right parahippocampal gyrus, and right middle temporal gyrus (BA 21). Women with MSI (but not those without MSI) showed significantly greater activation than men in the right posterior cingulate gyrus (BA 31) and greater deactivation in several frontal and temporal lobe areas. Conclusion: Men and women with CAD show differences in responses to stress in brain limbic areas that regulate emotion, and these functional responses differ by MSI status. Our results suggest that the cingulate gyrus may be involved in sex differences in MSI.
Bradykinin (BK) stimulates tissue plasminogen activator (t-PA) release from human endothelium. Although BK stimulates both nitric oxide and endothelium-derived hyperpolarizing factor (EDHF) release, the role of EDHF in t-PA release remains unexplored. This study sought to determine the mechanisms of BK-stimulated t-PA release in the forearm vasculature of healthy human subjects. Methods: In 33 healthy subjects (age 40.3 ± 1.9 years), forearm blood flow (FBF) and t-PA release were measured at rest and after intra-arterial infusions of BK (400 ng/min) and sodium nitroprusside (3.2 mg/min). Measurements were repeated after intra-arterial infusion of tetraethylammonium chloride (TEA; 1 μmol/min), fluconazole (0.4 μmol·min<sup>-1</sup>·l<sup>-1</sup>), and N<sup>G</sup>-monomethyl-L-arginine (L-NMMA, 8 μmol/min) to block nitric oxide, and their combination in separate studies. Results: BK significantly increased net t-PA release across the forearm (p < 0.0001). Fluconazole attenuated both BK-mediated vasodilation (-23.3 ± 2.7% FBF, p < 0.0001) and t-PA release (from 50.9 ± 9.0 to 21.3 ± 8.9 ng/min/100 ml, p = 0.02). TEA attenuated FBF (-14.7 ± 3.2%, p = 0.002) and abolished BK-stimulated t-PA release (from 22.9 ± 5.7 to -0.8 ± 3.6 ng/min/100 ml, p = 0.0002). L-NMMA attenuated FBF (p < 0.0001), but did not inhibit BK-induced t-PA release (nonsignificant). Conclusion: BK-stimulated t-PA release is partly due to cytochrome P<inf>450</inf>-derived epoxides and is inhibited by K<sup>+</sup><inf>Ca</inf> channel blockade. Thus, BK stimulates both EDHF-dependent vasodilation and t-PA release.