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Department of Medicine, Division of Cardiology, Emory University School of Medicine, Atlanta, GADepartment of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GAAtlanta VA Medical Center, Decatur, Georgia
Department of Medicine, Division of Cardiology, Emory University School of Medicine, Atlanta, GADepartment of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA
Address for Correspondence: Arshed A Quyyumi, MD, Emory Clinical Cardiovascular Research Institute, Emory University School of Medicine, 1462 Clifton Road N.E. Suite 507, Atlanta GA 30322, Phone: 404 727 3655; Fax: 404 712 8785;
Acute psychological stress can provoke mental stress (MS)-induced myocardial ischemia (MSIMI) in coronary artery disease (CAD). Stromal cell-derived factor 1 (SDF1) is released in response to hypoxia and higher levels of SDF1 are associated with adverse outcomes. We examined whether an increase in SDF1 level in response to MS predicts adverse outcomes in CAD patients.
Methods
554 patients with stable CAD (mean age 63, 76% male, 26% Black) underwent standardized MS testing. Plasma SDF1 levels were measured at rest and 90 minutes after MS, and MSIMI was evaluated by 99mTc-sestamibi perfusion imaging. Participants were followed for 5 years for the primary endpoint of composite of death and myocardial infarction (MI) and the secondary endpoint of as composite of death, myocardial infarction and heart failure hospitalization. Cox hazard models were used to assess the association between SDF1 change and incident adverse events.
Results
Mean (standard deviation) SDF1 change with MS was +56.0 (230) pg/mL. During follow-up, a rise of 1 SD in SDF1 with MS was associated with a 32% higher risk for the primary endpoint of death and MI (95%CI, 6-64%), independent of the resting SDF1 level, demographic and clinical risk factors and presence of ischemia. A rise of 1 SD in SDF1 was associated with 33% (95%CI, 11-59%) increase in the risk for the secondary endpoint independent of the resting SDF1 level, demographic and clinical risk factors and presence of ischemia. A
Conclusions
An increase in SDF1 level in response to MS is associated with a higher risk of adverse events in stable CAD, independent of MSIMI.
Stromal cell-derived factor 1 (SDF1), also known as CXCL12, is a chemokine that plays a central role in the recruitment of bone marrow progenitor cells for repair and regeneration in response to tissue ischemia.[
] and is subsequently released into plasma, creating a gradient of circulating SDF1 to facilitate the homing of progenitor cells to sites of ischemia to facilitate vasculogenesis.[
Stromal Cell–Derived Factor-1α Plays a Critical Role in Stem Cell Recruitment to the Heart After Myocardial Infarction but Is Not Sufficient to Induce Homing in the Absence of Injury.
] Other studies indicate that SDF1 participates not only in the maintenance of vascular homeostasis but also in the pathogenesis of various diseases including myocardial fibrosis.[
] Additionally, genomic studies have established a link between the CXCL12 genetic locus and both coronary artery disease (CAD) and myocardial infarction.[
We and others have demonstrated that higher circulating levels of SDF1 are associated with higher rates of adverse cardiovascular events in a variety of populations, including those with CAD. [
] Furthermore, we showed that SDF1 levels increase in response to exercise-induced transient ischemia in patients with CAD, and its magnitude is inversely correlated with the change in circulating progenitor cell levels, corroborating the mediating role of SDF1 for progenitor cell mobilization.[
] Mental stress-induced myocardial ischemia (MSIMI) is associated with greater coronary and peripheral microvascular constriction and may reflect susceptibility to recurrent mental stress episodes during life.[
In patients with stable CAD, we sought to examine 1) whether acute mental stress modulates circulating SDF1 levels and 2) whether the change in SDF1 level induced by mental stress has prognostic significance. We hypothesized that 1) SDF1 level changes during acute mental stress, and 2) an increase in circulating level of SDF1 in response to mental stress will be associated with a higher incidence risk of adverse cardiovascular events
METHODS
We prospectively recruited 695 adult patients aged 30-79 years with stable CAD between June 2011 and August 2014 from Emory University affiliated hospitals into the Mental Stress Ischemia Prognosis Study (MIPS). Stable CAD was defined by the presence of an abnormal coronary angiogram demonstrating atherosclerosis with luminal irregularities, or by the evidence of previous percutaneous or surgical coronary revascularization, prior myocardial infarction or a positive nuclear stress test. Exclusion criteria included evidence of acute coronary syndrome or decompensated heart failure within the prior two months, end-stage renal disease, or severe psychiatric conditions that could impact study assessments such as schizophrenia. Clinical information, such as previous CAD events, risk factors, and current medication use were obtained using standardized questionnaires and chart reviews. The study protocol complied with the Declaration of Helsinki and was approved by the Institutional Review Board of Emory University.
Subjects underwent mental stress tests with a standardized test protocol, as previously described.[
] A written informed consent as obtained from all subjects prior to inclusion in the study. Briefly, the testing procedure was performed in the morning after 12-hour fast, and all anti-anginal medications (beta blockers, calcium channel blockers, and long-acting nitrates), xanthine derivatives, and caffeine-containing products were withheld for 24 hours prior to the mental stress testing procedure.
We administered the protocol after a 30-minute rest period in a temperature-controlled (21-23°C), quiet and dimly lit room. Patients were asked to listen to a scripted message that provided instructions for the mental stress task. They were asked to imagine a stressful situation, using a scenario in which a close relative had been mistreated in a nursing home. They then were asked to prepare a statement for 2 minutes and then present it over 3 minutes period in front of a video camera and an audience wearing white coats. Patients were told that their speech would be evaluated for content and duration. Blood pressure and heart rate were recorded at 5-minute intervals during the resting phase and at 1-minute intervals during the mental stress period using an automatic oscillometer.
During the mental stress test, 20–30 mCi of the 99m-Tc radioisotope was administered at one minute into the speech. Myocardial perfusion imaging was obtained at rest and 30-60 minutes after mental stress with 99m-Tc-sestamibi single-photon emission computed tomography (SPECT) using standard nuclear imaging protocols.[
] Two experienced readers blinded to the other data of subjects read the images, and discrepancies in the interpretation were resolved by consensus. Rest and stress images were visually compared for the number and the severity of perfusion defects using a 17-segment model. Each segment was scored from 0 to 4, with 0 being normal uptake, and 4 no uptake. The development of MSIMI was defined as a new impairment with a score of ≥2 in any segment, or as worsening of a pre-existing impairment by at least 2 points if in a single segment, or by at least 1 point if in two or more contiguous segments.[
] Percent change in rate-pressure product (RPP) [systolic blood pressure heart rate] was calculated as the difference between the maximum value during the speech minus the minimum value during the rest period.
Venous blood samples were obtained at rest and 90 minutes after the mental stress testing procedure. Plasma was collected into ice-cooled citrate tubes, immediately followed by centrifuging at 4°C and snap-freezing at -70°C until further processing. The electrochemiluminescence MesoScale system (MesoScale Diagnostics, Rockville, MD) using the SECTOR Imager 2400 was used to quantify plasma SDF1 level. The lower limit of detection was 27.8 pg/mL, and the midpoint calibrator inter-assay coefficient of variation was 3.79% while the intra-assay coefficient of variation was 3.40%. Percent change in the plasma level of SDF1 was calculated and categorized into a greater increase (ΔSDF1>median) and a less increase (ΔSDF1≤median) for analysis.
Subjects were prospectively followed for adverse clinical outcomes, with follow-up data accrued from clinic visits at 1 and 2 years, by phone calls at 5 years, medical record review and querying the Social Security Death index. All events were adjudicated by study investigators who were blinded to other study data. The primary and secondary endpoints were composites respectively of death and MI and death, MI and HF hospitalization.
Descriptive data were summarized as mean ± standard deviation for continuous variables and as percentages for categorical variables. Two-sample t-tests for continuous variables and chi-square tests for categorical variables were performed to compare those with a greater increase in SDF1 (ΔSDF1>median) with those with less increase in SDF1 (ΔSDF1≤median) after the mental stress test.
We used multiple linear regression to examine independent predictors for the level of change in SDF1 with mental stress The covariates included demographic and medical history factors, including age, sex, race (Black vs. non-Black), body mass index (BMI), prior MI, smoking history, hypertension, hyperlipidemia, diabetes, HF, percent RPP change during mental stress, and the presence of MSIMI.
In the survival analysis, the Cox regression model was used to assess the joint association between the resting and the change in SDF1 level and adverse cardiovascular outcomes [Model 1]. Subsequent models were adjusted for the following variables: Model 2 for demographic and clinical factors (i.e., age, sex, race, BMI, hypertension, hyperlipidemia, diabetes, smoking history, prior MI and HF), Model 3 for the presence of MSIMI given that ischemia is a potent trigger for SDF1 release, Model 4 for the change in RPP as a known determinant of MSIMI, and Model 5 for education as a surrogate for socioeconomic status. We also compared event-free survival between those with a greater increase in SDF1 (ΔSDF1>median) and those with less increase in SDF1 (ΔSDF1≤median) using Kaplan-Meier curve. Finally, we compared event-free survival for both outcomes in the four groups with high and low resting, and high and low changes by median in SDF1 levels. All analyses were carried out using SAS (version 9.4, Cary, NC), and p <0.05 were considered statistically significant.
RESULTS
Among 695 patients with CAD recruited into the MIPS study, 2 patients were excluded due to a history of lupus vasculitis and sickle cell disease. A total of 609 had blood samples available for the measurement of resting SDF1 levels, and among these, 558 patients had SDF1 levels measured after mental stress testing. Four additional subjects were lost to follow-up (Supplemental Figure S1). Thus, in the final analytic cohort comprising of 554 patients, the mean age was 63.2 ± 8.9 years, 76% were male and 26% were Black (Table 1).
Table 1Baseline demographic and clinical characteristics stratified by the mental stress-induced change in plasma SDF1 level*.
Variables
All (N=558)
ΔSDF1≤ medianϑ (N=279)
ΔSDF1> median (N=279)
P-value
Baseline characteristics
Age, years
63.2 ± 8.9
63.4± 8.5
62.7 ± 9.4
0.36
Male
426 (76)
215 (77.1)
211 (75.6)
0.69
Black race
141 (26)
75 (27.6
66(23.7)
0.29
BMI, kg/m2
29.7 ± 5.2
29.16 ± 4.9
30.14 ± 5.6
0.026
Ever Smoking history
365 (58)
169 (61.2)
196 (57)
0.13
Hypertension
418 (75)
213 (76.34)
205 (73.48)
0.44
Diabetes mellitus
172 (31)
89 (31.9)
83 (29.75)
0.58
Hyperlipidemia
452 (81)
221 (79.21)
231 (82.8)
0.28
Prior CABG
186 (33)
90 (32.26)
96 (34.41)
0.59
Prior PTCA
304 (55)
155 (55.56)
149 (53.41)
0.61
Prior MI
201 (36)
93 (33.33)
109 (39.07)
0.16
Heart failure
122 (22)
60 (21.51)
62 (22.22)
0.84
Ejection fraction, %
55 ± 13
55.5 ± 13.7
55.1 ± 12.77
0.71
eGFR, mL/min/1.73m2
77 ± 18
94.6 ± 28
97.5 ± 32
0.26
Medication use
Aspirin
478 (86)
243 (87.41)
235 (84.23)
0.33
Beta blocker
410 (73)
205 (73.74)
205 (73.48)
0.94
Clopidogrel
195 (35)
90 (32.37)
105 (37.63)
0.19
Statin
474 (86)
232 (83.75)
242 (87.05)
0.27
ACE inhibitor
248 (44)
115 (41.52)
133 (47.84)
0.13
ARB
90 (16)
46 (16.55)
44 (15.77)
0.80
Calcium channel blocker
119 (21)
58 (20.86)
61 (21.86)
0.77
Mental stress testing related variables
% RPP change†
65 ± 37
64.8 ± 35
64.8 ± 38
0.96
Follow-up events
Death
51 (9.1)
23 (8.2)
28 (10.0)
0.46
Incidence rate (per 100 person-year)
1.5
1.3
1.7
0.37
MI
42 (7.7)
14 (5.0)
28 (10.0)
0.025
Incidence rate (per 100 person-year)
0.8
1.3
1.8
0.016
Hospitalization for HF
39 (7.0)
13 (4.7)
26 (9.3)
0.031
Incidence rate (per 100 person-year)
0.8
1.2
1.7
Composite endpoints
Death and myocardial infarction
92 (16.5)
38 (13.6)
54 (19.4)
0.068
Incidence rate (per 100 person-year)
2.3
2.9
3.4
0.062
Death, MI and HF hospitalization
114 (20.4)
46 (16.5)
68 (24.4)
0.021
Incidence rate (per 100 person-year)
2.7
3.7
4.7
0.0052
* Values are mean (SD) or n (%)
** Values are median _+/- interquartile range
ϑmedian SDF1 change = 56 pg/ml
† RPP (rate-pressure product) was defined by systolic blood pressure x heart rate. % Change was calculated as the maximum value during the mental stress test in comparison to the minimum value at rest.
Abbreviations: SDF1 = stromal cell-derived factor 1; BMI = body mass index; CABG = coronary artery bypass grafting; PTCA=percutaneous transluminal coronary angioplasty; MI = myocardial infarction; ACE = angiotensin converting enzyme, ARB = angiotensin II receptor blocker. RPP=rate pressure product.
The mean resting SDF1 level was 1296 ± 503 pg/mL (median 1258 pg/mL) and the mean change with mental stress was +56.0 (230) pg/mL (median 56 pg/mL). The demographic and clinical characteristics, including medication use, were similar in patients with either a high (>median) or low (<median) change in SDF1 level, except for a higher BMI in those with an increase in SDF1 level with mental stress (Table 1).
Of 554 subjects, 547 had SPECT images of adequate quality at rest and during the mental stress test to evaluate the development of MSIMI. A total of 88 (16%) patients developed MSIMI upon mental stress testing. Those with MSIMI had a significantly greater increase in SDF1 level with mental stress (8.3 ± 17.2 %) than those without MSIMI (4.1 ± 16.2 %; P=0.031) (Supplemental Figure S2). However, in a multiple linear regression model with adjustment for baseline demographic and clinical characteristics, higher BMI (β = 24.8, 95% confidence interval [CI] 6.5 –43.0) was the only independent predictor of a greater increase in SDF1 level with mental stress (Table 2).
Table 2Association between mental stress-induced change in stromal cell-derived factor 1 level and clinical variables*
Variables
Beta
95% C.I.
P-value
Age, per 10 years
-11.15
-32.59 to 10.29
0.31
Male
25.94
-19.05 to 70.94
0.26
Black race
17.52
-26.30 to 61.35
0.43
BMI, per 5kg/m2
24.78
6.54 to 43.04
0.0079
Prior MI
36.97
-2.74 to 76.68
0.068
Smoking history
-20.23
-59.12 to 18.67
0.31
Hypertension
-17.29
-61.42 to 26.84
0.44
Hyperlipidemia
5.19
-43.61 to 53.98
0.83
Diabetes mellitus
7.56
-33.90 to 49.01
0.36
Heart failure
5.57
-40.74 to 51.89
0.81
RPP change, per 10%
-3.13
-15.66 to 89.90
0.24
MSIMI
37.19
-15.66 to 89.90
0.17
Aspirin use
22.42
-32.51 to 77.36
0.42
* Change in SDF1 level was used as the dependent variable in multiple regression analysis.
Abbreviations: C.I.= confidence interval; BMI = body mass index; MI = myocardial infarction; eGFR = estimated glomerular filtration rate; RPP = Rate-pressure product; MSIMI = mental stress-induced myocardial ischemia
During a median follow-up duration of 5 years, 114 of 554 (18%) subjects suffered from at least one adverse cardiovascular event. As depicted in Kaplan Meier event-free survival curves, participants with a >median resting SDF1 level were at higher risk of adverse outcomes measured as a composite of death and myocardial infarction or as composite of death, myocardial infarction and heart failure hospitalization than those with ≤ median level, log-rank P = 0.031 and 0.0062, respectively (Figure 1A). Analyzed as a continuous variable using an unadjusted Cox regression model, a 1 SD higher resting SDF1 level was associated with a 24% higher risk of death and myocardial infarction and a 27% higher risk of death, myocardial infarction and heart failure hospitalization. (Table 3) Results remained significant when adjusted for demographic factors, clinical variables, resting SDF1 level, and the presence of MSIMI (Table 3).
Figure 1Kaplan Meier Curves for event-free survival of the primary (death and MI) and secondary endpoints (death, myocardial infarction and heart failure hospitalization). Figure A depicts the effect of resting level, low (≤ median) vs high (> median), and figure B depicts effect of change in SDF1 levels with mental stress, low (≤ median) vs high (> median). Comparison by log rank test. Abbreviations: SDF1 = stromal cell-derived factor-1; CV = cardiovascular; MI = myocardial infarction; HF = heart failure. Median baseline SDF1 = 1258 pg/ml and median SDF1 change = 56 pg/ml.
Table 3Association between the change and resting SDF1 level and the risk of adverse cardiovascular outcomes
Death / MI
Mental stress-Induced SDF1 change
Resting SDF1
HR*
95% C.I.
P-value
HR*
95% C.I.
P-value
Model 1†
1.26
1.04 –1.53
0.020
1.24
1.06–1.46
0.008
Model 2‡
1.33
1.07–1.65
0.010
1.26
1.05–1.51
0.009
Model 3§
1.32
1.06-1.64
0.012
1.28
1.07-1.54
0.008
Model 4#
1.31
1.06-1.63
0.014
1.27
1.05-1.52
0.012
Model 5τ
1.32
1.07-1.65
0.011
1.25
1.04-1.51
0.020
Death / MI / HF hospitalization
Mental stress-Induced SDF1 change
Resting SDF1
Model 1†
1.28
1.08- 1.51
0.004
1.27
1.07-1.50
0.006
Model 2‡
1.35
1.12-1.61
0.002
1.31
1.11-1.55
0.001
Model 3§
1.32
1.06-1.64
0.012
1.28
1.07-1.54
0.008
Model 4#
1.33
1.11-1.59
0.002
1.30
1.12-1.52
0.009
Model 5τ
1.34
1.12-1.60
0.002
1.30
1.10-1.54
0.002
* HR represents the risk of endpoints per 1 standard deviation for stress induced SDF1 change or resting level (SD for Delta SDF1= 230 pg/mL, SD for resting SDF=503 pg/mL).
†Model 1: Mental Stress-Induced Delta SDF1 adjusted for resting levels/ Resting levels adjusted for Mental Stress-Induced Delta SDF1.
‡Model 2: Model 1 + age, sex, race, smoking history, body mass index, prior MI, hypertension, diabetes, hyperlipidemia, and HF
§ Model 3: Model 2 + mental stress-induced ischemia
Patients with a greater increase in SDF1 level (ΔSDF1>median) with mental stress had a greater risk of adverse cardiovascular events (composite of death and myocardial infarction or death, myocardial infarction and heart failure hospitalization) than those with ≤median change, log-rank P= 0.0077 and 0.034, respectively (Figure 1). Analyzed as a continuous variable, a 1 SD rise in SDF1 level during mental stress was associated with a 26% higher risk of death and myocardial infarction and 28% higher risk of death, myocardial infarction and heart failure hospitalization, independent of resting levels. Results remained significant when adjusted for resting SDF1 level, demographic factors, clinical variables, RPP change during mental stress, and education (Table 3).
Because both resting and the change in SDF1 were independent and additive predictors of outcomes, we analyzed incident death and myocardial infarction in the four groups with high and low resting and high and low change (by median) in SDF1 levels. Patients with a greater rise in SDF1 level and higher resting SDF1 levels were at the highest risk for adverse events (P trend =0.024) compared to those with low resting and no change in SDF1 levels (Figure 2). Results were consistent when we assessed this association with death, myocardial infarction and heart failure hospitalization (P log-rank=0.00032), (Figure 2).
Figure 2Kaplan Meier Curves for event-free survival stratified by both resting and mental stress-induced changes in SDF1 levels. Figure A depicts death and myocardial infarction -free survival, and figure B depicts death, myocardial infarction and heart failure hospitalization -free survival. Comparison by log rank test. Abbreviations: SDF1 = stromal cell-derived factor1; CV = cardiovascular; MI = myocardial infarction; HF = heart failure.
In sensitivity analyses, the association between mental stress induced SDF1 change, and the study endpoints was largely similar across the subgroups stratified by age, sex, race, and prevalent HF (Supplemental Figure S3).
DISCUSSION
Herein, in a large cohort of patients with stable CAD, we examined the change in plasma SDF1 level in response to mental stress as a prognostic indicator of adverse cardiovascular outcomes. We demonstrated that 1) acute mental stress is associated with an increase in plasma SDF1 level, and 2) both resting and the magnitude of SDF1 level change with mental stress were independently and additively associated with the risk of incident adverse cardiovascular events. As presented in Supplemental Figure S4, these findings advance our mechanistic understanding of the role for mental stress-induced changes in circulating SDF1 levels as a determinant of adverse cardiovascular outcomes.
Our results suggest that the dynamic rise in circulating SDF1 level in laboratory-provoked mental stress reflects the tissue hypoxic injury and is prognostic for future adverse cardiovascular events independent of myocardial ischemia as detected by perfusion imaging. Several factors should be also considered in the interpretation of our results. First, the mental stress tests and resultant MSIMI in a laboratory setting have been reported to replicate mental stress and ischemia during the daily life of patients with CAD.[
] Thus, it is likely that an increase in SDF1 levels seen in our study occurs frequently in patients’ daily lives, reflective of the burden of MSIMI in their ambulatory setting. Secondly, given that the prognostic implication of SDF1 change was independent of MSIMI, there may be additional mechanistic pathways via which acute psychological stress mediates SDF1 level change, and ultimately adverse outcomes. For example, some studies recently reported that SDF1 level was elevated in patients under psychologically stressful conditions.[
Serum concentrations of chemokines (CCL-5 and CXCL-12), chemokine receptors (CCR-5 and CXCR-4), and IL-6 in patients with posttraumatic stress disorder and avoidant personality disorder.
Goyal, A., et al., Chronic Stress-Related Neural Activity Associates With Subclinical Cardiovascular Disease in Psoriasis: A Prospective Cohort Study. JACC Cardiovasc Imaging, 2018.
] It is plausible that increasing myocardial oxygen demand as a result of acute mental stress may stimulate SDF1 expression that in turn stimulates the recruitment of CXCR4+-expressing progenitor cells. We also found that exercise-induced ischemia inversely correlated SDF1 levels inversely correlate with progenitor cell counts.[
] In humans, SDF1 expression on platelets increases acutely and persists for up to 4 days in patients with acute coronary syndrome compared to those with stable disease.[
Expression of stromal-cell-derived factor-1 on circulating platelets is increased in patients with acute coronary syndrome and correlates with the number of CD34+ progenitor cells.
] Therefore, our finding of the mental stress-induced change in SDF1 level not only corroborates the current understanding of SDF1 activity with tissue ischemia/hypoxia, but provides evidence in humans regarding the psychological stress-induced increase in plasma SDF1 level.
Higher resting levels of SDF1 are known to be associated with incident cardiovascular events in patients with CAD,[
Higher plasma CXCL12 levels predict incident myocardial infarction and death in chronic kidney disease: findings from the Chronic Renal Insufficiency Cohort study.
] While SDF1 is a mediator of repair and regenerative angiogenesis in response to ischemic injury, and therefore cardio-protective, SDF1 has been also implicated in platelet aggregation[
There are some limitations to our findings. First, it is unclear whether 90 minutes is an optimal time for post-mental stress measurement of SDF1 level. Studies have shown changes in SDF1 expression in 30 minutes and plasma levels changing in 6 hours.[
] Second, this is a single center study using a single public speaking stressor protocol. Future replication studies using other mental stressors are needed for generalizability. Third, there is potential for selection bias because of outpatient recruitment of patients with stable CAD, measurement error due to protocol non-compliance, and misclassification. Fourth, our findings were limited to patients with CAD but may be different in subjects without underlying CAD. Finally, we did not assess CAD progression and personal stressors during the follow up period.
In a large cohort of patients with CAD, we demonstrate that higher resting levels and greater increase in the plasma level of SDF1 in response to acute psychologic stress are independently and additively associated with a higher risk of incident adverse cardiovascular outcomes, independent of MSIMI presence. Specific mechanisms by which mental stress induced SDF1 increase leads to adverse outcomes need further investigation.
Stromal Cell–Derived Factor-1α Plays a Critical Role in Stem Cell Recruitment to the Heart After Myocardial Infarction but Is Not Sufficient to Induce Homing in the Absence of Injury.
Serum concentrations of chemokines (CCL-5 and CXCL-12), chemokine receptors (CCR-5 and CXCR-4), and IL-6 in patients with posttraumatic stress disorder and avoidant personality disorder.
Goyal, A., et al., Chronic Stress-Related Neural Activity Associates With Subclinical Cardiovascular Disease in Psoriasis: A Prospective Cohort Study. JACC Cardiovasc Imaging, 2018.
Expression of stromal-cell-derived factor-1 on circulating platelets is increased in patients with acute coronary syndrome and correlates with the number of CD34+ progenitor cells.
Higher plasma CXCL12 levels predict incident myocardial infarction and death in chronic kidney disease: findings from the Chronic Renal Insufficiency Cohort study.
6Department of Epidemiology, University of Florida College of Medicine, Gainesville, FL
Both Drs Kim and Almuwaqqat contributed equally to this work
FUNDING
This work was supported by the National Institutes of Health (F32HL151163, P01 HL101398, P20HL113451-01, P01HL086773-06A1, R56HL126558-01, R01 HL109413, R01HL109413-02S1, UL1TR000454, TL1TR002382, UL1TR002378, KL2TR000455, K23HL127251, K24HL077506, K24 MH076955, and K12HD085850).
AUTHORS CONTRIBUTIONS:
J.H.K, A.J.S, J.D.B, V.V. and A.Q. contributed to study design. J.H.K, Z.A., C.L., M.H, K.M., S.S., L.W., Y.A.K., E.V.G, A.J.S, J.D.B, V.V., A.Q. contributed to acquisition, analysis, or interpretation of data. J.H.K, Z.A., C.L., M.H, K.M., S.S., P.R., B.P. L.W., Y.A.K.,E.V.G, A.J.S, J.D.B, V.V., A.Q. contributed to drafting of the manuscript: All authors participated in the critical review and revision of the manuscript
CONFLICT OF INTEREST
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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