JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
VOL. 65, NO. 3, 2015
ª 2015 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
ISSN 0735-1097/$36.00
PUBLISHED BY ELSEVIER INC.
Letters The Effect of Rosuvastatin on Platelet-Leukocyte Interactions in the Setting of Acute Coronary Syndrome
presentation to the University of Kentucky hospitals with symptoms and signs of ACS. Flow cytometry was performed on blood samples before (baseline), at 8 h, and at 24 h after placebo/or 40 mg rosuvastatin. Early administration of high-dose rosuvastatin resulted in a statistically significant reduction in circulating platelet-leukocyte aggregates over the
Statins have been used in the treatment of coronary
first 24 h (p ¼ 0.004). At the time of study enrollment
artery disease for 2 decades. In addition to long-
(baseline), the percent of leukocytes with associated
term protective effects elicited by lowering choles-
platelets was 39.8 4.9 (mean SEM) in the rosu-
terol, statins are postulated to have acute benefits
vastatin group and 29.2 3.8 in the placebo group.
in the setting of acute coronary syndromes (ACS)
Comparison of baseline revealed no significant dif-
and vascular injury. In the JUPITER (Justification
ference between the groups (p ¼ 0.132 following
for the Use of Statins in Prevention: an Intervention
Bonferroni adjustment). At 8 h after randomization,
Trial Evaluating Rosuvastatin) trial, rosuvastatin
the mean percent of platelet-leukocyte aggregates
reduced major adverse cardiovascular events in
was lower in the rosuvastatin group (21.1 3.2) than
patients with what historically was considered to be
in the placebo group (26.2 4.2). The absolute
normal cholesterol levels, and the best outcomes
reduction was 18.7% in the rosuvastatin group and
were observed in patients who had significant
only 3.0% in the placebo group at 8 h (p ¼ 0.0008
reduction in inflammation as indicated by lowering
for difference between doses from baseline to 8 h).
of C-reactive protein levels (1). Benefit of statin
At 24 h, the mean percent of platelet-leukocyte
therapy initiated 12 h prior to percutaneous coro-
aggregates was 21.3 2.8 in the rosuvastatin group
the
and 24.4 4.2 in the placebo group (p ¼ 0.0047
ARMYDA (Atorvastatin for Reduction of Myocardial
for difference between doses from baseline to 24 h).
Damage During Angioplasty) study, which measured
The percent of leukocytes with attached platelets
nary
intervention
was
demonstrated
in
biomarkers of cardiac injury after intervention.
from each patient within the groups (Figure 1A)
These and other findings suggest an effect inde-
and the respective fold change from baseline at
pendent of the lipid-lowering properties of statins
8 and 24 h (Figure 1B) demonstrates an overall
(2), although the precise mechanism of action re-
reduction in the proportion of leukocytes with
mains unknown. Platelet-leukocyte interactions in-
platelets in patients who received early, high-dose
crease
rosuvastatin.
in
the
setting
of
ACS
(3)
and
these
interactions correlate with, and may contribute to,
Our findings demonstrate that in the setting of
increased C-reactive protein levels and biomarkers
ACS, a high dose of rosuvastatin administered early
of myocardial necrosis (4). In animal models and in
in the hospital course can lead to significantly lower
vitro systems, statins have been demonstrated to
platelet-leukocyte heterotypic aggregates. The effect
reduce platelet-leukocyte interactions (5). To date,
was observed within 8 h of drug administration. This
no information is available on the effect of statin
study demonstrates a possible mechanism for the
therapy on platelet-leukocyte interactions in ACS or
acute benefit of statins in the setting of ACS and
other settings in humans.
provides a rationale to include high-dose statin
We conducted a prospective, double-blind study to
therapy as part of the standard of care for the initial
investigate the effect of high-dose rosuvastatin on
management of ACS.
the interactions between platelets and leukocytes
Travis R. Sexton, PhD Eric L. Wallace, DO Tracy E. Macaulay, PharmD Richard J. Charnigo, PhD Virgilio Evangelista, MD
in patients being admitted for ACS (Early Use of Rosuvastatin in Acute Coronary Syndromes: Targeting Platelet-Leukocyte Interactions; NCT01241903). Fifty-four subjects were identified within 8 h of
JACC VOL. 65, NO. 3, 2015
Letters
JANUARY 27, 2015:306–13
F I G U R E 1 Platelet-Leukocyte Aggregates in ACS Patients Randomized to Rosuvastatin or Placebo
B
100
Leukocyte-platelet Aggregates (Fold Change)
Leukocytes with Attached Platelets (%)
A
75
50
25
0
6 5 4 3 2 1 0
Baseline
8 Hour
24 Hour placebo
8 Hour
24 Hour
rosuvastatin
The percent of leukocytes with attached platelets for each subject is plotted at baseline, 8 h, and 24 h (A). The changes from baseline for each patient are shown (B). The horizontal bars indicate the mean of each sample set. Statistical significance was ascertained using a linear mixed model. ACS ¼ acute coronary syndrome(s).
Charles L. Campbell, MD Alison L. Bailey, MD *Susan S. Smyth, MD, PhD *The Gill Heart Institute University of Kentucky BBSRB B201 741 South Limestone Lexington, Kentucky 40506
3. Gawaz M, Neumann FJ, Ott I, Schiessler A, Schömig A. Platelet function in acute myocardial infarction treated with direct angioplasty. Circulation 1996; 93:229–37. 4. Zhang SZ, Jin YP, Qin GM, Wang JH. Association of platelet-monocyte aggregates with platelet activation, systemic inflammation, and myocardial injury in patients with non-ST elevation acute coronary syndromes. Clin Cardiol 2007;30:26–31. 5. Sanguigni V, Pignatelli P, Lenti L, et al. Short-term treatment with atorvastatin reduces platelet CD40 ligand and thrombin generation in hypercholesterolemic patients. Circulation 2005;111:412–9.
E-mail: [email protected] http://dx.doi.org/10.1016/j.jacc.2014.10.047 Please note: This work was supported by an investigator-initiated grant from AstraZeneca. Additional support was provided by the National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health, through Grant UL1TR000117. Dr. Sexton was supported in part by T32HL091812 from the Heart Lung and Blood Institute, National Institutes of Health. Dr. Charnigo has been a coinvestigator with Dr. Smyth on 2 grants from AstraZeneca. Dr. Bailey has received grant support from AstraZeneca. Dr. Smyth has previously served on advisory boards for AstraZeneca. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
REFERENCES
Infective Endocarditis Involving Apparently Structurally Normal Valves in Patients Without Previously Recognized Predisposing Heart Disease Recent temporal trend analyses have shown a sig-
1. Ridker PM, Fonseca FA, Genest J, et al., for the JUPITER Trial Study
nificant increase in infective endocarditis (IE) in pa-
Group. Baseline characteristics of participants in the JUPITER trial, a randomized placebo-controlled primary prevention trial of statin therapy among individuals with low low-density lipoprotein cholesterol and elevated high-sensitivity C-reactive protein. Am J Cardiol 2007;100: 1659–64.
tients without previously detected heart disease,
2. Patti G, Pasceri V, Colonna G, et al. Atorvastatin pretreatment improves outcomes in patients with acute coronary syndromes undergoing early percutaneous coronary intervention: results of the ARMYDA-ACS randomized
(1–4). This study was therefore designed to analyze echocardiographic data and surgical findings in
trial. J Am Coll Cardiol 2007;49:1272–8.
determining the underlying cardiac conditions.
but absence of imaging or surgical data for accurate evaluation of underlying heart disease resulted in incomplete
determination
of
clinical
features
307
VOL. 65, NO. 3, 2015
ª 2015 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
ISSN 0735-1097/$36.00
PUBLISHED BY ELSEVIER INC.
Letters The Effect of Rosuvastatin on Platelet-Leukocyte Interactions in the Setting of Acute Coronary Syndrome
presentation to the University of Kentucky hospitals with symptoms and signs of ACS. Flow cytometry was performed on blood samples before (baseline), at 8 h, and at 24 h after placebo/or 40 mg rosuvastatin. Early administration of high-dose rosuvastatin resulted in a statistically significant reduction in circulating platelet-leukocyte aggregates over the
Statins have been used in the treatment of coronary
first 24 h (p ¼ 0.004). At the time of study enrollment
artery disease for 2 decades. In addition to long-
(baseline), the percent of leukocytes with associated
term protective effects elicited by lowering choles-
platelets was 39.8 4.9 (mean SEM) in the rosu-
terol, statins are postulated to have acute benefits
vastatin group and 29.2 3.8 in the placebo group.
in the setting of acute coronary syndromes (ACS)
Comparison of baseline revealed no significant dif-
and vascular injury. In the JUPITER (Justification
ference between the groups (p ¼ 0.132 following
for the Use of Statins in Prevention: an Intervention
Bonferroni adjustment). At 8 h after randomization,
Trial Evaluating Rosuvastatin) trial, rosuvastatin
the mean percent of platelet-leukocyte aggregates
reduced major adverse cardiovascular events in
was lower in the rosuvastatin group (21.1 3.2) than
patients with what historically was considered to be
in the placebo group (26.2 4.2). The absolute
normal cholesterol levels, and the best outcomes
reduction was 18.7% in the rosuvastatin group and
were observed in patients who had significant
only 3.0% in the placebo group at 8 h (p ¼ 0.0008
reduction in inflammation as indicated by lowering
for difference between doses from baseline to 8 h).
of C-reactive protein levels (1). Benefit of statin
At 24 h, the mean percent of platelet-leukocyte
therapy initiated 12 h prior to percutaneous coro-
aggregates was 21.3 2.8 in the rosuvastatin group
the
and 24.4 4.2 in the placebo group (p ¼ 0.0047
ARMYDA (Atorvastatin for Reduction of Myocardial
for difference between doses from baseline to 24 h).
Damage During Angioplasty) study, which measured
The percent of leukocytes with attached platelets
nary
intervention
was
demonstrated
in
biomarkers of cardiac injury after intervention.
from each patient within the groups (Figure 1A)
These and other findings suggest an effect inde-
and the respective fold change from baseline at
pendent of the lipid-lowering properties of statins
8 and 24 h (Figure 1B) demonstrates an overall
(2), although the precise mechanism of action re-
reduction in the proportion of leukocytes with
mains unknown. Platelet-leukocyte interactions in-
platelets in patients who received early, high-dose
crease
rosuvastatin.
in
the
setting
of
ACS
(3)
and
these
interactions correlate with, and may contribute to,
Our findings demonstrate that in the setting of
increased C-reactive protein levels and biomarkers
ACS, a high dose of rosuvastatin administered early
of myocardial necrosis (4). In animal models and in
in the hospital course can lead to significantly lower
vitro systems, statins have been demonstrated to
platelet-leukocyte heterotypic aggregates. The effect
reduce platelet-leukocyte interactions (5). To date,
was observed within 8 h of drug administration. This
no information is available on the effect of statin
study demonstrates a possible mechanism for the
therapy on platelet-leukocyte interactions in ACS or
acute benefit of statins in the setting of ACS and
other settings in humans.
provides a rationale to include high-dose statin
We conducted a prospective, double-blind study to
therapy as part of the standard of care for the initial
investigate the effect of high-dose rosuvastatin on
management of ACS.
the interactions between platelets and leukocytes
Travis R. Sexton, PhD Eric L. Wallace, DO Tracy E. Macaulay, PharmD Richard J. Charnigo, PhD Virgilio Evangelista, MD
in patients being admitted for ACS (Early Use of Rosuvastatin in Acute Coronary Syndromes: Targeting Platelet-Leukocyte Interactions; NCT01241903). Fifty-four subjects were identified within 8 h of
JACC VOL. 65, NO. 3, 2015
Letters
JANUARY 27, 2015:306–13
F I G U R E 1 Platelet-Leukocyte Aggregates in ACS Patients Randomized to Rosuvastatin or Placebo
B
100
Leukocyte-platelet Aggregates (Fold Change)
Leukocytes with Attached Platelets (%)
A
75
50
25
0
6 5 4 3 2 1 0
Baseline
8 Hour
24 Hour placebo
8 Hour
24 Hour
rosuvastatin
The percent of leukocytes with attached platelets for each subject is plotted at baseline, 8 h, and 24 h (A). The changes from baseline for each patient are shown (B). The horizontal bars indicate the mean of each sample set. Statistical significance was ascertained using a linear mixed model. ACS ¼ acute coronary syndrome(s).
Charles L. Campbell, MD Alison L. Bailey, MD *Susan S. Smyth, MD, PhD *The Gill Heart Institute University of Kentucky BBSRB B201 741 South Limestone Lexington, Kentucky 40506
3. Gawaz M, Neumann FJ, Ott I, Schiessler A, Schömig A. Platelet function in acute myocardial infarction treated with direct angioplasty. Circulation 1996; 93:229–37. 4. Zhang SZ, Jin YP, Qin GM, Wang JH. Association of platelet-monocyte aggregates with platelet activation, systemic inflammation, and myocardial injury in patients with non-ST elevation acute coronary syndromes. Clin Cardiol 2007;30:26–31. 5. Sanguigni V, Pignatelli P, Lenti L, et al. Short-term treatment with atorvastatin reduces platelet CD40 ligand and thrombin generation in hypercholesterolemic patients. Circulation 2005;111:412–9.
E-mail: [email protected] http://dx.doi.org/10.1016/j.jacc.2014.10.047 Please note: This work was supported by an investigator-initiated grant from AstraZeneca. Additional support was provided by the National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health, through Grant UL1TR000117. Dr. Sexton was supported in part by T32HL091812 from the Heart Lung and Blood Institute, National Institutes of Health. Dr. Charnigo has been a coinvestigator with Dr. Smyth on 2 grants from AstraZeneca. Dr. Bailey has received grant support from AstraZeneca. Dr. Smyth has previously served on advisory boards for AstraZeneca. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
REFERENCES
Infective Endocarditis Involving Apparently Structurally Normal Valves in Patients Without Previously Recognized Predisposing Heart Disease Recent temporal trend analyses have shown a sig-
1. Ridker PM, Fonseca FA, Genest J, et al., for the JUPITER Trial Study
nificant increase in infective endocarditis (IE) in pa-
Group. Baseline characteristics of participants in the JUPITER trial, a randomized placebo-controlled primary prevention trial of statin therapy among individuals with low low-density lipoprotein cholesterol and elevated high-sensitivity C-reactive protein. Am J Cardiol 2007;100: 1659–64.
tients without previously detected heart disease,
2. Patti G, Pasceri V, Colonna G, et al. Atorvastatin pretreatment improves outcomes in patients with acute coronary syndromes undergoing early percutaneous coronary intervention: results of the ARMYDA-ACS randomized
(1–4). This study was therefore designed to analyze echocardiographic data and surgical findings in
trial. J Am Coll Cardiol 2007;49:1272–8.
determining the underlying cardiac conditions.
but absence of imaging or surgical data for accurate evaluation of underlying heart disease resulted in incomplete
determination
of
clinical
features
307
