International Journal of Cardiology 172 (2014) e6–e8
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Letter to the Editor
Interleukin-10 in patients with ST-segment elevation myocardial infarction☆,☆☆ Raquel Appa Falcao a,b, Sanah Christopher a,b, Claudia Oddi a,b, Leonid Reznikov c, John D. Grizzard a,b, Nayef A. Abouzaki a,b, Amit Varma a,b, Benjamin W. Van Tassell a,b, Charles A. Dinarello c, Antonio Abbate a,b,⁎ a b c
Virginia Commonwealth University, VCU Pauley Heart Center, Richmond, VA, USA Victoria Johnson Research Laboratories, Richmond, VA, USA University of Colorado, Department of Medicine, Aurora, CO, USA
a r t i c l e
i n f o
Article history: Received 2 October 2013 Accepted 20 December 2013 Available online 5 January 2014 Keywords: Inflammation Interleukin Myocardial infarction Remodeling
To the Editor: Acute myocardial infarction (AMI) is characterized by an intense inflammatory response [1]. The production of pro-inflammatory cytokines (interleukin-1β [IL-1β], tumor necrosis factor-α [TNF-α], IL-6) dominates in the earlier phases, and endogenous anti-inflammatory cytokines (IL-1 receptor antagonist [IL-1Ra] IL-18BP and IL-10) quench the acute inflammation [1]. IL-10 is a naturally occurring anti-inflammatory cytokine produced by leukocytes [2]. In experimental AMI, lower tissue levels of IL-10 were associated with progression to heart failure [3]. Clinical studies in patients with AMI, however, are inconsistent on the prognostic value of circulating IL-10 plasma levels with studies showing that higher IL-10 levels predict a more favorable outcome, whereas others show that higher IL-10 predict recurrent cardiac events or heart failure [see supplemental references 1–12 for a comprehensive list]. Single determinations of plasma levels have limitations related to variation in timing of sampling, degree and extent of heart injury, and co-morbidities. Therefore, higher IL-10 plasma levels may be seen in ☆ Clinical trials registration: www.clinicaltrials.gov (NCT01175018). ☆☆ Funding: This study was funded by an American Heart Association Scientist Development Grant (10SDG 3030051) to Dr. Abbate. Dr. Van Tassell was supported by an Institutional National Institute of Health K12 award (KL2RR031989). Dr. Dinarello was supported by a National Institute of Health grant (AI-15614). ⁎ Corresponding author at: VCU Pauley Heart Center, Virginia Commonwealth University Box 980281, room 10-41, 1200 E. Broad Street, Richmond, VA 23298, USA. 0167-5273/$ – see front matter © 2014 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ijcard.2013.12.126
subjects with larger infarcts and the predictive value of IL-10 levels may be attenuated by such confounders. To overcome this limitation, we studied a small cohort of subjects with more homogeneous clinical characteristics and used a whole blood culture assay expressing the production of cytokine per million white blood cells over 24 h as possibly a better indicator of inflammatory status [4]. The objective of this study was, indeed, to measure spontaneous production of IL-10 from leukocytes derived from patients with AMI in culture and to analyze the correlation with plasma levels of IL-10 with adverse cardiac remodeling. The study included a subgroup of 13 patients with acute ST-segment elevation MI enrolled in a prospective clinical trial [5]. Inclusion criteria included pain onset of b 12 h, ST-segment elevation on ECG and successful primary percutaneous coronary revascularization. Exclusion criteria included lack of informed consent; cardiac arrest; hemodynamic instability; prior Q wave infarction or pre-existing congestive heart failure stage C/D — NYHA class IV, LV ejection fraction of b20%, or severe aortic or mitral valve disease; contraindications to magnetic resonance imaging; pregnancy; chronic infections, autoinflammatory or autoimmune disease, or cancer; and recent (b 14 days) use of anti-inflammatory drugs (non-steroidal anti-inflammatory drugs excluded) [5]. We collected peripheral blood samples obtained at 72 h after onset of symptoms in all patients and levels of IL-10 were determined using multiplex immunoassay (Human Cytokine Mosaic, R&D Systems, Minneapolis, MN). Whole blood samples were incubated at 37 °C for 24 h to determine the leukocyte production of IL-10 over 24 h. After 24 h, the cells were lysed with Triton X, and the lysate was assayed using the same multiplex immunoassay. Fig. 1 shows a scheme of sample processing [4]. A cardiac magnetic resonance (CMR) study was performed 24–96 h after admission and 10–14 weeks later, using a Siemens Avanto 1.5 Tesla magnet, as described earlier [5]. Briefly, contiguous 6 mm steady-state free precession cine images with 2 mm gaps were obtained from the mitral valve ring through the cardiac apex. LVESV, LVEDV, and LVEF were computed by tracing the LV contours using this stack of 10–12 short-axis slices and aided by the software CMR42 (Circle Cardiovascular Imaging, Calgary, Canada). To visualize areas of infarction and no reflow, late gadolinium enhancement imaging was performed, beginning 10 min post-contrast administration. The infarct size was calculated using the CMR42 software using the full-width-at-half-maximum technique. Dimensions were indexed (i) to body surface area. All
R.A. Falcao et al. / International Journal of Cardiology 172 (2014) e6–e8
Incubated at 37°C for 24 h
e7
IL-10 production in vitro
Comparison between IL10 production and plasma levels
Plasma IL-10 levels
30
LVESVi change (ml/m2)
LVEDVi change (ml/m2)
10
R=+0.60 P=0.049
20
10 0
-10
R=+0.33 P=0.31
5
0
5
-10
-20 2
3
4
5
6
2
3
Plasma IL-10 (pg/ml)
4
5
6
Plasma IL-10 (pg/ml) 10
R=-0.92 P
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Letter to the Editor
Interleukin-10 in patients with ST-segment elevation myocardial infarction☆,☆☆ Raquel Appa Falcao a,b, Sanah Christopher a,b, Claudia Oddi a,b, Leonid Reznikov c, John D. Grizzard a,b, Nayef A. Abouzaki a,b, Amit Varma a,b, Benjamin W. Van Tassell a,b, Charles A. Dinarello c, Antonio Abbate a,b,⁎ a b c
Virginia Commonwealth University, VCU Pauley Heart Center, Richmond, VA, USA Victoria Johnson Research Laboratories, Richmond, VA, USA University of Colorado, Department of Medicine, Aurora, CO, USA
a r t i c l e
i n f o
Article history: Received 2 October 2013 Accepted 20 December 2013 Available online 5 January 2014 Keywords: Inflammation Interleukin Myocardial infarction Remodeling
To the Editor: Acute myocardial infarction (AMI) is characterized by an intense inflammatory response [1]. The production of pro-inflammatory cytokines (interleukin-1β [IL-1β], tumor necrosis factor-α [TNF-α], IL-6) dominates in the earlier phases, and endogenous anti-inflammatory cytokines (IL-1 receptor antagonist [IL-1Ra] IL-18BP and IL-10) quench the acute inflammation [1]. IL-10 is a naturally occurring anti-inflammatory cytokine produced by leukocytes [2]. In experimental AMI, lower tissue levels of IL-10 were associated with progression to heart failure [3]. Clinical studies in patients with AMI, however, are inconsistent on the prognostic value of circulating IL-10 plasma levels with studies showing that higher IL-10 levels predict a more favorable outcome, whereas others show that higher IL-10 predict recurrent cardiac events or heart failure [see supplemental references 1–12 for a comprehensive list]. Single determinations of plasma levels have limitations related to variation in timing of sampling, degree and extent of heart injury, and co-morbidities. Therefore, higher IL-10 plasma levels may be seen in ☆ Clinical trials registration: www.clinicaltrials.gov (NCT01175018). ☆☆ Funding: This study was funded by an American Heart Association Scientist Development Grant (10SDG 3030051) to Dr. Abbate. Dr. Van Tassell was supported by an Institutional National Institute of Health K12 award (KL2RR031989). Dr. Dinarello was supported by a National Institute of Health grant (AI-15614). ⁎ Corresponding author at: VCU Pauley Heart Center, Virginia Commonwealth University Box 980281, room 10-41, 1200 E. Broad Street, Richmond, VA 23298, USA. 0167-5273/$ – see front matter © 2014 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ijcard.2013.12.126
subjects with larger infarcts and the predictive value of IL-10 levels may be attenuated by such confounders. To overcome this limitation, we studied a small cohort of subjects with more homogeneous clinical characteristics and used a whole blood culture assay expressing the production of cytokine per million white blood cells over 24 h as possibly a better indicator of inflammatory status [4]. The objective of this study was, indeed, to measure spontaneous production of IL-10 from leukocytes derived from patients with AMI in culture and to analyze the correlation with plasma levels of IL-10 with adverse cardiac remodeling. The study included a subgroup of 13 patients with acute ST-segment elevation MI enrolled in a prospective clinical trial [5]. Inclusion criteria included pain onset of b 12 h, ST-segment elevation on ECG and successful primary percutaneous coronary revascularization. Exclusion criteria included lack of informed consent; cardiac arrest; hemodynamic instability; prior Q wave infarction or pre-existing congestive heart failure stage C/D — NYHA class IV, LV ejection fraction of b20%, or severe aortic or mitral valve disease; contraindications to magnetic resonance imaging; pregnancy; chronic infections, autoinflammatory or autoimmune disease, or cancer; and recent (b 14 days) use of anti-inflammatory drugs (non-steroidal anti-inflammatory drugs excluded) [5]. We collected peripheral blood samples obtained at 72 h after onset of symptoms in all patients and levels of IL-10 were determined using multiplex immunoassay (Human Cytokine Mosaic, R&D Systems, Minneapolis, MN). Whole blood samples were incubated at 37 °C for 24 h to determine the leukocyte production of IL-10 over 24 h. After 24 h, the cells were lysed with Triton X, and the lysate was assayed using the same multiplex immunoassay. Fig. 1 shows a scheme of sample processing [4]. A cardiac magnetic resonance (CMR) study was performed 24–96 h after admission and 10–14 weeks later, using a Siemens Avanto 1.5 Tesla magnet, as described earlier [5]. Briefly, contiguous 6 mm steady-state free precession cine images with 2 mm gaps were obtained from the mitral valve ring through the cardiac apex. LVESV, LVEDV, and LVEF were computed by tracing the LV contours using this stack of 10–12 short-axis slices and aided by the software CMR42 (Circle Cardiovascular Imaging, Calgary, Canada). To visualize areas of infarction and no reflow, late gadolinium enhancement imaging was performed, beginning 10 min post-contrast administration. The infarct size was calculated using the CMR42 software using the full-width-at-half-maximum technique. Dimensions were indexed (i) to body surface area. All
R.A. Falcao et al. / International Journal of Cardiology 172 (2014) e6–e8
Incubated at 37°C for 24 h
e7
IL-10 production in vitro
Comparison between IL10 production and plasma levels
Plasma IL-10 levels
30
LVESVi change (ml/m2)
LVEDVi change (ml/m2)
10
R=+0.60 P=0.049
20
10 0
-10
R=+0.33 P=0.31
5
0
5
-10
-20 2
3
4
5
6
2
3
Plasma IL-10 (pg/ml)
4
5
6
Plasma IL-10 (pg/ml) 10
R=-0.92 P
