- Email: [email protected]
Platelet Activation and Myocardial Infarction in Patients With Pneumonia
1488
JACC VOL. 65, NO. 14, 2015
Letters
APRIL 14, 2015:1484–94
activation prior to CAP should be considered as a significant limitation of the study that possibly confounds its results. In addition, the editorial by Santos-Gallego and Badimon (2) raises an important question regarding the role of platelet aggregation as a risk factor or a
Platelet Activation and Myocardial Infarction in Patients With Pneumonia Are Statins the Answer?
risk marker in these entities. However, platelet aggregation was not assessed in the present study, which utilized only soluble markers of platelet
In this population-based cohort study, Cangemi et al.
reactivity Platelet activation is an ongoing and
(1) found that increased platelet activation and
continuous process that is better represented by
thromboxane overproduction was associated with
ex vivo markers, such as homotypic and heterotypic
myocardial infarction in patients with pneumonia.
platelet aggregation. The gold standard method for
Moreover, they also suggested that aspirin alone was
estimation of heterotypic platelet aggregation is
insufficient
considered the measurement of monocyte-platelet
Although, the study is observational in nature, it adds
aggregates (MPA) assessed by flow cytometry. MPA
to already accumulated evidence that suggests
have been proven a robust and reproducible in vivo
increased cardiovascular events with infection and
marker of platelet activation (5), even in the clinical
sepsis (2). Statins with their anti-inflammatory and
setting (5), and could have been used in order to
antithrombotic effects may play a role in the treatment
assess more accurately the extend of platelet reac-
of pneumonia and prevent associated cardiovascular
tivity and to understand the role of platelet func-
complications. Statins have been shown, not only to
tion, and more than that, the role of antiplatelet
inhibit thromboxane synthesis (3), but to also do so in
therapy.
case of incomplete inhibition by aspirin (4). Statins
to
inhibit
thromboxane
production.
In conclusion, a number of factors should be taken
also decrease P-selectin and soluble CD40 ligand, both
into consideration before establishing a connection
of which play a role in atherosclerosis and consequent
between CAP, platelet activation, and MI. Platelets’
cardiovascular events. Epidemiological evidence has
pathophysiological interplay between inflammation
shown a beneficial effect in the treatment of pneu-
and thrombosis suggested by in vitro studies needs
monia (5). However, the available evidence is weak
to be further investigated in well-designed clinical
because it is based on observational design. Given the
studies with robust platelet activation markers.
biological plausibility of the association, randomized controlled trials are needed to define the role of statins
Eleni Gavriilaki, MD, MSc *Eugenia Gkaliagkousi, MD, PhD Stella Douma, MD
in the treatment of pneumonia and its associated
*Hippokration General Hospital
*Abdur Rahman Khan, MD Aref A. Bin Abdulhak, MD Faraz Khan Luni, MD Ragheb Assaly, MD
54643 Thessaloniki Greece E-mail: [email protected] http://dx.doi.org/10.1016/j.jacc.2014.11.073
cardiovascular complications.
*Department of Internal Medicine University of Toledo
REFERENCES 1. Cangemi R, Casciaro M, Rossi E, et al., for the SIXTUS Study Group. Platelet activation is associated with myocardial infarction in patients with pneumonia. J Am Coll Cardiol 2014;64:1917–25. 2. Santos-Gallego CG, Badimon JJ. The sum of two evils: pneumonia and myocardial infarction: is platelet activation the missing link? J Am Coll Cardiol 2014;64:1926–8. 3. Chatzidimitriou D, Kirmizis D, Gavriilaki E, Chatzidimitriou M, Malisiovas N. Atherosclerosis and infection: is the jury still not in? Future Microbiol 2012;7: 1217–30. 4. Lim WS, Baudouin SV, George RC, et al. BTS guidelines for the management of community acquired pneumonia in adults: update 2009. Thorax 2009;64 Suppl 3:iii1–55. 5. Gkaliagkousi E, Passacquale G, Douma S, Zamboulis C, Ferro A. Platelet activation in essential hypertension: implications for antiplatelet treatment. Am J Hypertens 2010;23:229–36.
Health Sciences Campus 3000 Arlington Avenue Toledo, Ohio 43614 E-mail: [email protected] http://dx.doi.org/10.1016/j.jacc.2014.11.074
REFERENCES 1. Cangemi R, CM, Rossi E, et al., for the SIXTUS Study Group. Platelet activation is associated with myocardial infarction in patients with pneumonia. J Am Coll Cardiol 2014;64:1917–25. 2. Smeeth L, Thomas SL, Hall AJ, Hubbard R, Farrington P, Vallance P. Risk of myocardial infarction and stroke after acute infection or vaccination. N Engl J Med 2004;351:2611–8. 3. Undas A, Siudak Z, Topor-Madry R, Lesniak M, Tracz W. Simvastatin administration reduces thromboxane production in subjects taking aspirin:
JACC VOL. 65, NO. 14, 2015
Letters
APRIL 14, 2015:1484–94
links between aspirin resistance and thrombin generation. Int J Cardiol 2012; 154:59–64. 4. Eikelboom JW, Hankey GJ, Thom J, et al., Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management and Avoidance (CHARISMA) Investigators. Incomplete inhibition of thromboxane biosynthesis by acetylsalicylic acid: determinants and effect on cardiovascular risk. Circu-
that most patients with CAP disclosed non–STsegment elevation MI, indicating that type II MI and, therefore, coronary vasoconstriction might have an important role in favoring myocardial ischemia. We agree with the authors that the concomitant
lation 2008;118:1705–12.
presence of cardiovascular disease or atherosclerotic
5. Khan AR, Riaz M, Bin Abdulhak AA, et al. The role of statins in prevention and treatment of community acquired pneumonia: a systematic review and meta-analysis. PloS One 2013;8:e52929.
risk factors could account for platelet activation detected at admission, but its significant reduction, observed at discharge, points to a role of CAP in favoring platelet activation. The mechanism(s) ac-
REPLY: Platelets Interplay Between Pneumonia and Cardiovascular Events
counting for CAP-related platelet activation were not investigated in the study and consequently may be
Establishing a Link?
only a matter of speculation. Analysis of more
Platelet Activation and Myocardial Infarction
sophisticated markers of platelet activation will
in Patients With Pneumonia
certainly help to provide more insight into the role
Are Statins the Answer?
of platelets as a determinant of myocardial ischemia in pneumonia. However, we believe that at this
We thank Dr. Gavrillaki and colleagues for the comments related to our recent paper (1) demonstrating a significant association between in vivo platelet activation and myocardial infarction (MI) in 278 patients affected by community-acquired pneumonia (CAP) and suggesting a potential role for platelets in precipitating coronary ischemia. Dr. Gavrillaki and colleagues raise some issues that need to be addressed. The authors question the putative interplay between infections and MI overall because interventional trials with antibiotics failed to show a reduction of MI. However, trials with antibiotics have serious clinical and methodological limitations regarding dosages of the antibiotics, wide variation in sample size and follow-up, and limited use of antibiotics (essentially macrolides and fluoroquinolone) (2). Furthermore, interventional trials with antibiotics have been performed in patients with stable or acute coronary heart disease on the assumption that microorganisms, in particular Chlamydia pneumoniae, are implicated in atherosclerosis initiation and progression (2). Hence, it is methodologically inappropriate to extrapolate from these findings that infections cannot precipitate MI because these clinical settings are different in terms of clinical course, concomitant treatment, and very likely, mechanism of disease from CAP-related MI. In this context, it is clinically relevant that pneumonia severity score was a strong predictor of MI, indicating that the severity of infection and/or inflammation plays a key role in favoring myocardial ischemia. Platelet activation may be one mechanism through which CAP precipitates MI via a process of coronary thrombosis and/or vasoconstriction. We don’t have conclusive data on this issue, but it is interesting to underscore
moment, it is more crucial to know whether platelet activation represents a mere epiphenomenon of CAP or has a role in triggering coronary thrombosis and/or vasoconstriction. Thus, interventional trials with aspirin or other antiplatelet drugs could be of interest to investigate whether platelets actually have a role in precipitating MI in patients with pneumonia. Interestingly, Dr. Khan and colleagues, in their letter, suggest that statins may be an intriguing alternative because they possess antiplatelet activity, and a recent meta-analysis demonstrated a potential role of statins in reducing CAP-related mortality (3). We agree with this hypothesis because statins disclose an early and late antiplatelet effect, which is mediated
by
down-regulation
of
Nox2-derived
oxidative stress and lipid-lowering activity, respectively (4). Nox2 down-regulation may be of interest because in patients with CAP Nox2, the most important cellular producer of oxygen free radicals, is up-regulated and associated with myocardial damage and ischemia (5). Furthermore, statins amplify the platelet response to aspirin by reducing platelet eicosanoid formation, namely isoprostanes and thromboxane A2, and could, in turn, be useful in case of incomplete COX1 inhibition by aspirin (4). Hence, statins may be tested as an alternative to aspirin or on top of aspirin to assess whether they are able to reduce cardiac complications in patients with CAP. *Francesco Violi, MD Camilla Calvieri, MD Marco Falcone, MD Gloria Taliani, MD Roberto Cangemi, MD on behalf of the SIXTUS Study Group
1489
JACC VOL. 65, NO. 14, 2015
Letters
APRIL 14, 2015:1484–94
activation prior to CAP should be considered as a significant limitation of the study that possibly confounds its results. In addition, the editorial by Santos-Gallego and Badimon (2) raises an important question regarding the role of platelet aggregation as a risk factor or a
Platelet Activation and Myocardial Infarction in Patients With Pneumonia Are Statins the Answer?
risk marker in these entities. However, platelet aggregation was not assessed in the present study, which utilized only soluble markers of platelet
In this population-based cohort study, Cangemi et al.
reactivity Platelet activation is an ongoing and
(1) found that increased platelet activation and
continuous process that is better represented by
thromboxane overproduction was associated with
ex vivo markers, such as homotypic and heterotypic
myocardial infarction in patients with pneumonia.
platelet aggregation. The gold standard method for
Moreover, they also suggested that aspirin alone was
estimation of heterotypic platelet aggregation is
insufficient
considered the measurement of monocyte-platelet
Although, the study is observational in nature, it adds
aggregates (MPA) assessed by flow cytometry. MPA
to already accumulated evidence that suggests
have been proven a robust and reproducible in vivo
increased cardiovascular events with infection and
marker of platelet activation (5), even in the clinical
sepsis (2). Statins with their anti-inflammatory and
setting (5), and could have been used in order to
antithrombotic effects may play a role in the treatment
assess more accurately the extend of platelet reac-
of pneumonia and prevent associated cardiovascular
tivity and to understand the role of platelet func-
complications. Statins have been shown, not only to
tion, and more than that, the role of antiplatelet
inhibit thromboxane synthesis (3), but to also do so in
therapy.
case of incomplete inhibition by aspirin (4). Statins
to
inhibit
thromboxane
production.
In conclusion, a number of factors should be taken
also decrease P-selectin and soluble CD40 ligand, both
into consideration before establishing a connection
of which play a role in atherosclerosis and consequent
between CAP, platelet activation, and MI. Platelets’
cardiovascular events. Epidemiological evidence has
pathophysiological interplay between inflammation
shown a beneficial effect in the treatment of pneu-
and thrombosis suggested by in vitro studies needs
monia (5). However, the available evidence is weak
to be further investigated in well-designed clinical
because it is based on observational design. Given the
studies with robust platelet activation markers.
biological plausibility of the association, randomized controlled trials are needed to define the role of statins
Eleni Gavriilaki, MD, MSc *Eugenia Gkaliagkousi, MD, PhD Stella Douma, MD
in the treatment of pneumonia and its associated
*Hippokration General Hospital
*Abdur Rahman Khan, MD Aref A. Bin Abdulhak, MD Faraz Khan Luni, MD Ragheb Assaly, MD
54643 Thessaloniki Greece E-mail: [email protected] http://dx.doi.org/10.1016/j.jacc.2014.11.073
cardiovascular complications.
*Department of Internal Medicine University of Toledo
REFERENCES 1. Cangemi R, Casciaro M, Rossi E, et al., for the SIXTUS Study Group. Platelet activation is associated with myocardial infarction in patients with pneumonia. J Am Coll Cardiol 2014;64:1917–25. 2. Santos-Gallego CG, Badimon JJ. The sum of two evils: pneumonia and myocardial infarction: is platelet activation the missing link? J Am Coll Cardiol 2014;64:1926–8. 3. Chatzidimitriou D, Kirmizis D, Gavriilaki E, Chatzidimitriou M, Malisiovas N. Atherosclerosis and infection: is the jury still not in? Future Microbiol 2012;7: 1217–30. 4. Lim WS, Baudouin SV, George RC, et al. BTS guidelines for the management of community acquired pneumonia in adults: update 2009. Thorax 2009;64 Suppl 3:iii1–55. 5. Gkaliagkousi E, Passacquale G, Douma S, Zamboulis C, Ferro A. Platelet activation in essential hypertension: implications for antiplatelet treatment. Am J Hypertens 2010;23:229–36.
Health Sciences Campus 3000 Arlington Avenue Toledo, Ohio 43614 E-mail: [email protected] http://dx.doi.org/10.1016/j.jacc.2014.11.074
REFERENCES 1. Cangemi R, CM, Rossi E, et al., for the SIXTUS Study Group. Platelet activation is associated with myocardial infarction in patients with pneumonia. J Am Coll Cardiol 2014;64:1917–25. 2. Smeeth L, Thomas SL, Hall AJ, Hubbard R, Farrington P, Vallance P. Risk of myocardial infarction and stroke after acute infection or vaccination. N Engl J Med 2004;351:2611–8. 3. Undas A, Siudak Z, Topor-Madry R, Lesniak M, Tracz W. Simvastatin administration reduces thromboxane production in subjects taking aspirin:
JACC VOL. 65, NO. 14, 2015
Letters
APRIL 14, 2015:1484–94
links between aspirin resistance and thrombin generation. Int J Cardiol 2012; 154:59–64. 4. Eikelboom JW, Hankey GJ, Thom J, et al., Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management and Avoidance (CHARISMA) Investigators. Incomplete inhibition of thromboxane biosynthesis by acetylsalicylic acid: determinants and effect on cardiovascular risk. Circu-
that most patients with CAP disclosed non–STsegment elevation MI, indicating that type II MI and, therefore, coronary vasoconstriction might have an important role in favoring myocardial ischemia. We agree with the authors that the concomitant
lation 2008;118:1705–12.
presence of cardiovascular disease or atherosclerotic
5. Khan AR, Riaz M, Bin Abdulhak AA, et al. The role of statins in prevention and treatment of community acquired pneumonia: a systematic review and meta-analysis. PloS One 2013;8:e52929.
risk factors could account for platelet activation detected at admission, but its significant reduction, observed at discharge, points to a role of CAP in favoring platelet activation. The mechanism(s) ac-
REPLY: Platelets Interplay Between Pneumonia and Cardiovascular Events
counting for CAP-related platelet activation were not investigated in the study and consequently may be
Establishing a Link?
only a matter of speculation. Analysis of more
Platelet Activation and Myocardial Infarction
sophisticated markers of platelet activation will
in Patients With Pneumonia
certainly help to provide more insight into the role
Are Statins the Answer?
of platelets as a determinant of myocardial ischemia in pneumonia. However, we believe that at this
We thank Dr. Gavrillaki and colleagues for the comments related to our recent paper (1) demonstrating a significant association between in vivo platelet activation and myocardial infarction (MI) in 278 patients affected by community-acquired pneumonia (CAP) and suggesting a potential role for platelets in precipitating coronary ischemia. Dr. Gavrillaki and colleagues raise some issues that need to be addressed. The authors question the putative interplay between infections and MI overall because interventional trials with antibiotics failed to show a reduction of MI. However, trials with antibiotics have serious clinical and methodological limitations regarding dosages of the antibiotics, wide variation in sample size and follow-up, and limited use of antibiotics (essentially macrolides and fluoroquinolone) (2). Furthermore, interventional trials with antibiotics have been performed in patients with stable or acute coronary heart disease on the assumption that microorganisms, in particular Chlamydia pneumoniae, are implicated in atherosclerosis initiation and progression (2). Hence, it is methodologically inappropriate to extrapolate from these findings that infections cannot precipitate MI because these clinical settings are different in terms of clinical course, concomitant treatment, and very likely, mechanism of disease from CAP-related MI. In this context, it is clinically relevant that pneumonia severity score was a strong predictor of MI, indicating that the severity of infection and/or inflammation plays a key role in favoring myocardial ischemia. Platelet activation may be one mechanism through which CAP precipitates MI via a process of coronary thrombosis and/or vasoconstriction. We don’t have conclusive data on this issue, but it is interesting to underscore
moment, it is more crucial to know whether platelet activation represents a mere epiphenomenon of CAP or has a role in triggering coronary thrombosis and/or vasoconstriction. Thus, interventional trials with aspirin or other antiplatelet drugs could be of interest to investigate whether platelets actually have a role in precipitating MI in patients with pneumonia. Interestingly, Dr. Khan and colleagues, in their letter, suggest that statins may be an intriguing alternative because they possess antiplatelet activity, and a recent meta-analysis demonstrated a potential role of statins in reducing CAP-related mortality (3). We agree with this hypothesis because statins disclose an early and late antiplatelet effect, which is mediated
by
down-regulation
of
Nox2-derived
oxidative stress and lipid-lowering activity, respectively (4). Nox2 down-regulation may be of interest because in patients with CAP Nox2, the most important cellular producer of oxygen free radicals, is up-regulated and associated with myocardial damage and ischemia (5). Furthermore, statins amplify the platelet response to aspirin by reducing platelet eicosanoid formation, namely isoprostanes and thromboxane A2, and could, in turn, be useful in case of incomplete COX1 inhibition by aspirin (4). Hence, statins may be tested as an alternative to aspirin or on top of aspirin to assess whether they are able to reduce cardiac complications in patients with CAP. *Francesco Violi, MD Camilla Calvieri, MD Marco Falcone, MD Gloria Taliani, MD Roberto Cangemi, MD on behalf of the SIXTUS Study Group
1489