Association Between Platelet Aggregation and Mental Stress
Induced Myocardial Ischemia: Results From the REMIT Trial
Robert W. Harrison, MD; Richard C. Becker, MD; Thomas L. Ortel, MD, PhD; Maragatha Kuchibhatla, PhD; Stephen H. Boyle, PhD; Zainab Samad, MD; Eric J. Velazquez, MD;
Jennifer Wilson, BA; Cynthia Kuhn, PhD; Redford B. Williams, MD; Christopher M. O’Connor, MD; Wei Jiang, MD
Duke University, Durham, NC
Results
Background
Variable
• Platelet activation is an important factor in
acute coronary syndromes, and patients with
depression and hostility have increased
platelet reactivity. However, an association
between platelet reactivity and MSIMI has not
been established1
Objectives
• Assess platelet aggregation before and after
mental stress testing in patients with known
coronary heart disease
Methods
REMIT
• NHLBI sponsored randomized clinical trial
designed to assess the efficacy of
escitalopram on MSIMI in patients with
established coronary artery disease
• Eligible patients: Adults with clinically stable
coronary heart disease (prior stenosis > 70%,
or history of myocardial infarction or
revascularization)
Study Procedure
• Subjects were administered a series of 3
mental tasks: 1) mental arithmetic, 2) public
speaking with anger recall, and 3) mirror
tracing
• Blood samples were collected before and after
mental stress testing to assess platelet
aggregation
Table 2: Baseline resting platelet aggregation
Table 1: Baseline characteristics
Normal LV response
N=49
MSIMI
N=105
P-value
Demographics
Age, mean (SD), years
61.2 (9.4)
63.1 (10.9)
0.54
Gender (Female)
2 (4.1)
19 (18.1)
0.02
Race (Non-White)
5 (10.2)
22 (21.0)
0.10
Medical History
• Hypothesis: Patients who are susceptible to
MSIMI will have increased mental stress
induced platelet aggregation compared to
those without MSIMI
Platelet Aggregation
• Aggregation determined with a BIO-DATA 4channel platelet aggregometer. Variables of
interest included the area under the platelet
aggregation curve (AUC) and the maximal
amplitude of platelet aggregation (%)
• Aggregation triggered by epinephrine (1, 2, 5,
an 10 µM), collagen (1, 2, 5, and 10 µM),
adenosine diphosphate (ADP; 1, 2, µM), and
each agonist with serotonin (5HT; 10 µM)
MSIMI
N=105
Mean (SD)
P-value
ADP 5 µM
239.1 (127.5)
237.5 (110.0)
0.94
Epinephrine, 10 µM
147.1 (146.0)
139.5 (81.8)
0.73
Ortel, JL: Honoraria; Boehringer Ingelheim,
Instrumentation Laboratories. Research
Grants; Pfizer, Eisai, and GSK
Collagen, 10 µM
273.1 (102.1)
278.6 (95.6)
0.75
Kuchibhatla, M: None
Serotonin, 5 µM+ ADP, 1 µM
211.7 (119.0)
206.0 (105.0)
0.77
Area Under the Curve (% x minutes)
16 (32.7)
28 (26.7)
0.44
Serotonin, 5 µM+ Epinephrine, 2 µM
243.9 (97.3)
242.3 (89.7)
0.92
Current Angina
10 (20.4)
22 (21.0)
0.95
Serotonin, 5 µM + Collagen, 2 µM
232.1 (107.4)
235.9 (91.3)
0.83
Maximal Amplitude (%)
Boyle, SH: None
Samad, Z: None
Velazquez, EJ: Honoraria; Novartis.
Speaker’s Bureau; Gilead. Research
Grants; Abbott-Vascular
Prior Myocardial Infarction
15 (30.6)
53 (50.5)
0.07
Prior PCI
28 (57.1)
65 (61.9)
0.57
ADP 5 µM
53.6 (22.4)
52.5 (20.7)
0.77
Prior CABG
22 (44.9)
52 (49.5)
0.59
Epinephrine, 10 µM
28.5 (18.0)
29.6 (15.8)
0.71
Wilson, J: None
1 (2.0)
7 (6.67)
0.23
Collagen, 10 µM
67.0 (23.1)
66.7 (19.6)
0.93
Kuhn, C: None
Hypertension
38 (77.6)
79 (75.2)
0.75
Serotonin, 5 µM+ ADP, 1 µM
50.0 (20.7)
47.9 (18.7)
0.53
Hyperlipidemia
47 (95.9)
97 (92.4)
0.41
Serotonin, 5 µM+ Epinephrine, 2 µM
53.6 (18.3)
52.5 (18.1)
0.73
Williams, RB:
Ownership/Partnership/Principal;
Williams LifeSkills, Inc.
Current Tobacco Use
4 (8.2)
19 (18.1)
0.27
Serotonin, 5 µM + Collagen, 2 µM
52.0 (23.4)
52.9 (19.9)
0.83
Depression
5 (10.2)
19 (18.1)
0.21
55.5 (8.7)
53.3 (11.0)
0.21
Congestive Heart Failure
Baseline Ejection Fraction,
mean (SD), %
Figure: Adjusted change in platelet aggregation following mental stress
40
20
Medications
Endpoints:
• MSIMI: a decrease in EF of ≥ 8% or a new focal
wall motion abnormality induced by mental
stress testing
Aspirin
47 (95.9)
102 (98.1)
0.44
Additional Antiplatelet
20 (40.8)
49 (47.1)
0.47
ACE-I
35 (71.4)
69 (66.4)
0.53
ARB
3 (6.1)
16 (15.4)
0.11
• Normal left ventricular response (NLVR): No
change or an increase in EF, and no focal wall
motion abnormalities in response to mental
stress testing
Calcium Channel Blocker
9 (18.8)
18 (17.3)
0.83
-60
Beta blocker
38 (77.6)
93 (89.4)
0.051
10
Statin
46 (93.9)
99 (95.2)
0.73
• Future work should investigate whether or not
antiplatelet therapy could be protective against
mental stress induced myocardial ischemia in
susceptible patients
Becker, RC: Honoraria; Bristol-Myers
Squibb, Sanofi-Aventis, Boehringer
Ingelheim. Research Grants; Bristol-Myers
Squibb, Bayer Pharmaceuticals, Johns and
Johnson, Regado Biosciences, and
AstraZeneca
Normal LV response
N=49
Mean (SD)
Diabetes
Conclusions
• Mental stress testing resulted in increased
platelet aggregation, as measured by the AUC
and maximal amplitude, in patients who are
susceptible to mental stress induced ischemia
Agonist
References: 1Jiang, W. et al Responses of mental stress induced myocardial ischemia to escitalopram
treatment: Background, design, and method for the Responses of Mental Stress Induced Myocardial
Ischemia to Escitalopram Treatment trial. Am Heart J. 2012; 163:20-6
2Jiang
W, et al. Prevalence and clinical characteristics of mental stress-induced myocardial ischemia in
patients with coronary heart disease. J Am Coll Cardiol. 2013; 61:714-722
∆ AUC
• MSIMI was more common than exercise
induced myocardial ischemia in the REMIT
trial, affecting 43% of patients with coronary
heart disease2
• Patients with MSIMI have a poorer prognosis
than those who do not exhibit MSIMI1
*
*
*
NLVR
MSIMI
*
0
O’Connor, CM: Honoraria; Novella,
Cardiology Consulting Associates, Amgen.
Ownership/Partnership/ Principal;
Biscardia LLC. Research Grants; Otsuka,
Roche Diagnostics, BG Medicine, Critical
Diagnostics, Astellas, Gilead, GE
Healthcare, ResMed
Jiang, W: None
Sponsorship:
National Heart, Lung, and Blood Institute
grant number RHL085704
-20
-40
∆ Maximal Amplitude
• Patients with coronary heart disease are
susceptible to mental stress-induced
myocardial ischemia (MSIMI), and patients
susceptible to MSIMI have a poorer prognosis1
Disclosures:
Harrison, RW: None
5
ADP
*
EPI
Coll
*
5HT + ADP
5HT + Epi
*
0
-5
-10
-15
Data are presented as least squares mean and standard error of the mean after
adjustment for gender, baseline EF, and baseline platelet aggregation. *= P < 0.05
MSIMI vs. NLVR
5HT+ Coll
Contact
Robert W. Harrison, MD
Duke Clinical Research Institute
Durham, NC 27705
Robert.w.harrison@duke.edu