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Beneficial effects of statin treatment after myocardial infarction: Is progenitor cell mobilization the missing link?
International Journal of Cardiology 130 (2008) 301 – 303 www.elsevier.com/locate/ijcard
Editorial Comment
Beneficial effects of statin treatment after myocardial infarction: Is progenitor cell mobilization the missing link? ☆ Dimitris Tousoulis a,⁎, Juan Carlos Kaski b , Charalambos Antoniades a , Christodoulos Stefanadis a b
a Cardiology Department, Athens University Medical School, Greece Cardiac and Vascular Sciences, St George's Hospital, University of London, UK
Received 19 April 2008; accepted 28 June 2008 Available online 20 August 2008
Abstract It is widely accepted that statin treatment improves survival in patients with myocardial infarction. Evidence also suggests that aggressive statin treatment is superior than standard dose during the post-infarction period. However, the exact mechanisms are still not well understood. Endothelial progenitor cells (EPC) play a key role in vascular homeostasis, since they contribute to the repair of damaged endothelium postmyocardial infarction, while they induce neoangiogenesis. Recent evidence suggests that statins may exert their beneficial effect in patients with recent myocardial infarction, by inducing EPC mobilization, and this may be a key mechanism by which statins improve survival in these patients. However, large scale clinical trials remain to prove that aggressive statin treatment is superior than standard dose in these patients, by inducing a more effective EPC mobilization. © 2008 Elsevier Ireland Ltd. All rights reserved. Keywords: Statins; Endothelial progenitor cells; Myocardial infarction; Inflammation
1. Introduction In an elegant clinical study published in this issue of IJC, Leone et al. [1] compared the effect of low- vs high-dose atorvastatin treatment on endothelial progenitor cell (EPC) mobilization and left ventricular (LV) function in patients with post-myocardial infarction (MI). They report that an intensive statin treatment after primary or rescue percutaneous intervention is associated with a higher EPC count at follow up as compared to standard treatment post-MI. This
☆ Invited Editorial for submission IJC-D-08-00277, entitled “Effect of intensive vs standard statin therapy on endothelial progenitor cells and left ventricular function in patients with acute myocardial infarction: The STRAP trial”, by Leone et al. ⁎ Corresponding author. Vasilissis Sofias 114, 115 28, Athens, Greece. Tel.: +302109624833. E-mail address: [email protected] (D. Tousoulis).
0167-5273/$ - see front matter © 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2008.06.079
interesting study raises important questions regarding both the role of EPCs in acute ischemic heart disease and the effects of statin treatment on EPCs and other prognostic markers in patients with acute coronary syndromes. 2. Statins in acute coronary syndromes The beneficial effect of lipid lowering treatment on cardiovascular mortality has been demonstrated by several large scale mortality and morbidity trials [2–4]. In the acute coronary syndrome setting, it was shown that prescription of statins in the first days after acute MI is associated with lower hospital mortality [5]. Other studies [4,6–8] in patients with acute coronary syndromes showed that prescription of a lipid lowering drug at hospital discharge was independently associated with reduced short-term mortality. In the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) study [9] atorvastatin therapy
302
D. Tousoulis et al. / International Journal of Cardiology 130 (2008) 301–303
was associated with a significant reduction in the composite endpoint of death, non fatal myocardial infarction, resuscitated sudden death, or urgent readmission for worsening angina compared with placebo. In view of these data, it is now crucial to define the exact mechanisms by which statins exert these beneficial effects during the acute coronary syndromes in humans. Studies from our lab [10,11] and others [12] have demonstrated that early initiation of low-dose atorvastatin treatment decreases inflammatory [10] and thrombotic processes [11] during the first weeks after unstable angina or myocardial infarction [13]. It has also been demonstrated that statins affect multiple mechanisms involved in vascular homeostasis post-MI, since they improve nitric oxide bioavailability and improve vascular redox in patients with MI [10,12]. 3. Statins and EPCs mobilization: benefits on myocardial function in animal models Further to their important role in myocardial redox signalling and vascular function, evidence suggests that statins also improve neoangiogenesis in human myocardium [14]. This may result in the improvement of myocardial perfusion and systemic haemodynamics [15]. Statins increase EPC number and functional activity [16] thereby contributing to re-endothelialization of the injured vessels [17]. In addition, statins enhance NO bioavailability and exert potent anti-inflammatory and antioxidant effects beyond cholesterol reduction, properties that may contribute to the favorable impact of statins on EPCs [18], as NO is a key signalling molecule for EPC mobilization [19]. Indeed, animal studies have demonstrated that statins can induce EPCs mobilization from the bone marrow thus enhancing neovascularization [16]. It has also been suggested that this effect of statins may be mediated by the rapid activation of Akt protein kinase in EPCs, enhancing proliferative and migratory activities and cell survival [16]. In line to these initial observations, more recent studies conducted in animal models of MI [20], suggested that statin therapy normalizes increased reactive oxygen species generation and it also enhances bone marrow vascular endothelial growth factor (VEGF) protein levels, Akt phosphorylation, endothelial nitric oxide synthase (eNOS) activity, and EPC mobilization. This EPC mobilization [20], during the early post-MI phase, was associated with improved cardiac function and increased capillary density in the peri-infarct area 7 days after MI. However, the enhancement of EPC levels in response to statin treatment were sustained 10 weeks post-infarction, but still it is unknown whether statins exert similar effects in humans. 4. Statins, EPCs mobilization and myocardial function: from bench to bedsite In the study by Leone et al. [1] in post-MI patients, intensive atorvastatin treatment induced EPC mobilization compared to
standard dose treatment. However, in contrary with previous reports [15] suggesting that statin treatment improves myocardial contractility, Leone et al. [1] failed to demonstrate a superior effect of intensive treatment on myocardial contractility and the overall hemodynamic profile. Possible explanations for this discrepancy include: 1) The Leone findings are indeed correct and thus intensive statin treatment is not superior to the standard dose, regarding its effects on myocardial function post-MI. However, the Leone study [1] did not include a placebo-control group, probably due to ethical reasons, as statin treatment is recommended by the current guidelines for the treatment of patients with recent MI [21], and this is a major limitation of this study. 2) All patients in the Leone [1] study underwent primary or rescue angioplasty, thus achieving rapid myocardial revascularization, limiting in this way the true biological effect of internal neovascularization on the recovery of infarcted myocardium. 3) Limitations in the study design, such as the small number of participants, along with the ultrasound method used to calculate ejection fraction – i.e. the ultrasound Simpson's method – may have limited the ability of detecting any borderline effect on myocardial contractility, that might have been present. 5. Conclusions The importance of statin treatment on the survival of patients post-MI is now well established. Statin treatment decreases morbidity and mortality of patients with acute coronary syndromes, but the mechanisms responsible for these effects – particularly on myocardial function – are not well characterized. As EPC mobilization plays a crucial role in neovascularization in human myocardium post-MI, and statin treatment is a major stimuli for EPCs mobilization, it is likely that statins may indeed have a crucial effect on the functional recovery of infarcted myocardium. The Leone study [1] provided new insights into the interaction between high-dose statin treatment, EPC mobilization and myocardial function during the post-MI period. However, further large scale clinical trials are needed to further examine the effect of intensive statin treatment on myocardial function and to identify the exact role of EPCs in this setting. References [1] Leone AM, Rutella S, Giannico MB, et al. Effect of intensive vs standard statin therapy on endothelial progenitor cells and left ventricular function in patients with acute myocardial infarction: STatins for Regeneration after Acute myocardial infarction and PCI (STRAP) trial. Int J Cardiol 2008;130:157–62. [2] Krum H, Latini R, Maggioni AP, et al. Statins and symptomatic chronic systolic heart failure: a post-hoc analysis of 5010 patients enrolled in Val-HeFT. Int J Cardiol 2007;119:48–53. [3] Anker SD, Clark AL, Winkler R, et al. Statin use and survival in patients with chronic heart failure—results from two observational studies with 5200 patients. Int J Cardiol 2006;112:234–42. [4] Newby LK, Kristinsson A, Bhapkar MV, et al. Early statin initiation and outcomes in patients with acute coronary syndromes. Jama 2002;287:3087–95.
D. Tousoulis et al. / International Journal of Cardiology 130 (2008) 301–303 [5] Laufs U, La Fata V, Plutzky J, Liao JK. Upregulation of endothelial nitric oxide synthase by HMG CoA reductase inhibitors. Circulation 1998;97:1129–35. [6] Aronow HD, Topol EJ, Roe MT, et al. Effect of lipid-lowering therapy on early mortality after acute coronary syndromes: an observational study. Lancet 2001;357:1063–8. [7] Kinlay S, Schwartz GG, Olsson AG, et al. Effect of atorvastatin on risk of recurrent cardiovascular events after an acute coronary syndrome associated with high soluble CD40 ligand in the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) Study. Circulation 2004;110:386–91. [8] Kinlay S, Schwartz GG, Olsson AG, et al. High-dose atorvastatin enhances the decline in inflammatory markers in patients with acute coronary syndromes in the MIRACL Study. Circulation 2003;108:1560–6. [9] Schwartz GG, Olsson AG, Ezekowitz MD, et al. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL Study: a randomized controlled trial. JAMA 2001;285:1711–8. [10] Tousoulis D, Antoniades C, Katsi V, et al. The impact of early administration of low-dose atorvastatin treatment on inflammatory process, in patients with unstable angina and low cholesterol level. Int J Cardiol 2006;109:48–52. [11] Tousoulis D, Bosinakou E, Kotsopoulou M, Antoniades C, Katsi V, Stefanadis C. Effects of early administration of atorvastatin treatment on thrombotic process in normocholesterolemic patients with unstable angina. Int J Cardiol 2006;106:333–7. [12] Spin JM, Vagelos RH. Early use of statins in acute coronary syndromes. Curr Cardiol Rep 2002;4:289–97. [13] Stefanadi E, Tousoulis D, Antoniades C, et al. Early initiation of lowdose atorvastatin treatment after an acute ST-elevated myocardial
[14] [15]
[16]
[17]
[18] [19]
[20]
[21]
303
infarction, decreases inflammatory process and prevents endothelial injury and activation. Int J Cardiol in press. Ma FX, Han ZC. Statins, nitric oxide and neovascularization. Cardiovasc Drug Rev 2005;23:281–92. Gurgun C, Ildizli M, Yavuzgil O, et al. The effects of short term statin treatment on left ventricular function and inflammatory markers in patients with chronic heart failure. Int J Cardiol 2008;123:102–7. Llevadot J, Murasawa S, Kureishi Y, et al. HMG-CoA reductase inhibitor mobilizes bone marrow-derived endothelial progenitor cells. J Clin Invest 2001;108:399–405. Walter DH, Rittig K, Bahlmann FH, et al. Statin therapy accelerates reendothelialization: a novel effect involving mobilization and incorporation of bone marrow-derived endothelial progenitor cells. Circulation 2002;105:3017–24. Endres M. Statins: potential new indications in inflammatory conditions. Atheroscler Suppl 2006;7:31–5. Landmesser U, Engberding N, Bahlmann FH, et al. Statin-induced improvement of endothelial progenitor cell mobilization, myocardial neovascularization, left ventricular function, and survival after experimental myocardial infarction requires endothelial nitric oxide synthase. Circulation 2004;110:1933–9. Thum T, Fraccarollo D, Galuppo P, et al. Bone marrow molecular alterations after myocardial infarction: impact on endothelial progenitor cells. Cardiovasc Res 2006;70:50–60. Antman EM, Hand M, Armstrong PW, et al. 2007 focused update of the ACC/AHA 2004 guidelines for the management of patients with ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2008;51:210–47.
Editorial Comment
Beneficial effects of statin treatment after myocardial infarction: Is progenitor cell mobilization the missing link? ☆ Dimitris Tousoulis a,⁎, Juan Carlos Kaski b , Charalambos Antoniades a , Christodoulos Stefanadis a b
a Cardiology Department, Athens University Medical School, Greece Cardiac and Vascular Sciences, St George's Hospital, University of London, UK
Received 19 April 2008; accepted 28 June 2008 Available online 20 August 2008
Abstract It is widely accepted that statin treatment improves survival in patients with myocardial infarction. Evidence also suggests that aggressive statin treatment is superior than standard dose during the post-infarction period. However, the exact mechanisms are still not well understood. Endothelial progenitor cells (EPC) play a key role in vascular homeostasis, since they contribute to the repair of damaged endothelium postmyocardial infarction, while they induce neoangiogenesis. Recent evidence suggests that statins may exert their beneficial effect in patients with recent myocardial infarction, by inducing EPC mobilization, and this may be a key mechanism by which statins improve survival in these patients. However, large scale clinical trials remain to prove that aggressive statin treatment is superior than standard dose in these patients, by inducing a more effective EPC mobilization. © 2008 Elsevier Ireland Ltd. All rights reserved. Keywords: Statins; Endothelial progenitor cells; Myocardial infarction; Inflammation
1. Introduction In an elegant clinical study published in this issue of IJC, Leone et al. [1] compared the effect of low- vs high-dose atorvastatin treatment on endothelial progenitor cell (EPC) mobilization and left ventricular (LV) function in patients with post-myocardial infarction (MI). They report that an intensive statin treatment after primary or rescue percutaneous intervention is associated with a higher EPC count at follow up as compared to standard treatment post-MI. This
☆ Invited Editorial for submission IJC-D-08-00277, entitled “Effect of intensive vs standard statin therapy on endothelial progenitor cells and left ventricular function in patients with acute myocardial infarction: The STRAP trial”, by Leone et al. ⁎ Corresponding author. Vasilissis Sofias 114, 115 28, Athens, Greece. Tel.: +302109624833. E-mail address: [email protected] (D. Tousoulis).
0167-5273/$ - see front matter © 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2008.06.079
interesting study raises important questions regarding both the role of EPCs in acute ischemic heart disease and the effects of statin treatment on EPCs and other prognostic markers in patients with acute coronary syndromes. 2. Statins in acute coronary syndromes The beneficial effect of lipid lowering treatment on cardiovascular mortality has been demonstrated by several large scale mortality and morbidity trials [2–4]. In the acute coronary syndrome setting, it was shown that prescription of statins in the first days after acute MI is associated with lower hospital mortality [5]. Other studies [4,6–8] in patients with acute coronary syndromes showed that prescription of a lipid lowering drug at hospital discharge was independently associated with reduced short-term mortality. In the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) study [9] atorvastatin therapy
302
D. Tousoulis et al. / International Journal of Cardiology 130 (2008) 301–303
was associated with a significant reduction in the composite endpoint of death, non fatal myocardial infarction, resuscitated sudden death, or urgent readmission for worsening angina compared with placebo. In view of these data, it is now crucial to define the exact mechanisms by which statins exert these beneficial effects during the acute coronary syndromes in humans. Studies from our lab [10,11] and others [12] have demonstrated that early initiation of low-dose atorvastatin treatment decreases inflammatory [10] and thrombotic processes [11] during the first weeks after unstable angina or myocardial infarction [13]. It has also been demonstrated that statins affect multiple mechanisms involved in vascular homeostasis post-MI, since they improve nitric oxide bioavailability and improve vascular redox in patients with MI [10,12]. 3. Statins and EPCs mobilization: benefits on myocardial function in animal models Further to their important role in myocardial redox signalling and vascular function, evidence suggests that statins also improve neoangiogenesis in human myocardium [14]. This may result in the improvement of myocardial perfusion and systemic haemodynamics [15]. Statins increase EPC number and functional activity [16] thereby contributing to re-endothelialization of the injured vessels [17]. In addition, statins enhance NO bioavailability and exert potent anti-inflammatory and antioxidant effects beyond cholesterol reduction, properties that may contribute to the favorable impact of statins on EPCs [18], as NO is a key signalling molecule for EPC mobilization [19]. Indeed, animal studies have demonstrated that statins can induce EPCs mobilization from the bone marrow thus enhancing neovascularization [16]. It has also been suggested that this effect of statins may be mediated by the rapid activation of Akt protein kinase in EPCs, enhancing proliferative and migratory activities and cell survival [16]. In line to these initial observations, more recent studies conducted in animal models of MI [20], suggested that statin therapy normalizes increased reactive oxygen species generation and it also enhances bone marrow vascular endothelial growth factor (VEGF) protein levels, Akt phosphorylation, endothelial nitric oxide synthase (eNOS) activity, and EPC mobilization. This EPC mobilization [20], during the early post-MI phase, was associated with improved cardiac function and increased capillary density in the peri-infarct area 7 days after MI. However, the enhancement of EPC levels in response to statin treatment were sustained 10 weeks post-infarction, but still it is unknown whether statins exert similar effects in humans. 4. Statins, EPCs mobilization and myocardial function: from bench to bedsite In the study by Leone et al. [1] in post-MI patients, intensive atorvastatin treatment induced EPC mobilization compared to
standard dose treatment. However, in contrary with previous reports [15] suggesting that statin treatment improves myocardial contractility, Leone et al. [1] failed to demonstrate a superior effect of intensive treatment on myocardial contractility and the overall hemodynamic profile. Possible explanations for this discrepancy include: 1) The Leone findings are indeed correct and thus intensive statin treatment is not superior to the standard dose, regarding its effects on myocardial function post-MI. However, the Leone study [1] did not include a placebo-control group, probably due to ethical reasons, as statin treatment is recommended by the current guidelines for the treatment of patients with recent MI [21], and this is a major limitation of this study. 2) All patients in the Leone [1] study underwent primary or rescue angioplasty, thus achieving rapid myocardial revascularization, limiting in this way the true biological effect of internal neovascularization on the recovery of infarcted myocardium. 3) Limitations in the study design, such as the small number of participants, along with the ultrasound method used to calculate ejection fraction – i.e. the ultrasound Simpson's method – may have limited the ability of detecting any borderline effect on myocardial contractility, that might have been present. 5. Conclusions The importance of statin treatment on the survival of patients post-MI is now well established. Statin treatment decreases morbidity and mortality of patients with acute coronary syndromes, but the mechanisms responsible for these effects – particularly on myocardial function – are not well characterized. As EPC mobilization plays a crucial role in neovascularization in human myocardium post-MI, and statin treatment is a major stimuli for EPCs mobilization, it is likely that statins may indeed have a crucial effect on the functional recovery of infarcted myocardium. The Leone study [1] provided new insights into the interaction between high-dose statin treatment, EPC mobilization and myocardial function during the post-MI period. However, further large scale clinical trials are needed to further examine the effect of intensive statin treatment on myocardial function and to identify the exact role of EPCs in this setting. References [1] Leone AM, Rutella S, Giannico MB, et al. Effect of intensive vs standard statin therapy on endothelial progenitor cells and left ventricular function in patients with acute myocardial infarction: STatins for Regeneration after Acute myocardial infarction and PCI (STRAP) trial. Int J Cardiol 2008;130:157–62. [2] Krum H, Latini R, Maggioni AP, et al. Statins and symptomatic chronic systolic heart failure: a post-hoc analysis of 5010 patients enrolled in Val-HeFT. Int J Cardiol 2007;119:48–53. [3] Anker SD, Clark AL, Winkler R, et al. Statin use and survival in patients with chronic heart failure—results from two observational studies with 5200 patients. Int J Cardiol 2006;112:234–42. [4] Newby LK, Kristinsson A, Bhapkar MV, et al. Early statin initiation and outcomes in patients with acute coronary syndromes. Jama 2002;287:3087–95.
D. Tousoulis et al. / International Journal of Cardiology 130 (2008) 301–303 [5] Laufs U, La Fata V, Plutzky J, Liao JK. Upregulation of endothelial nitric oxide synthase by HMG CoA reductase inhibitors. Circulation 1998;97:1129–35. [6] Aronow HD, Topol EJ, Roe MT, et al. Effect of lipid-lowering therapy on early mortality after acute coronary syndromes: an observational study. Lancet 2001;357:1063–8. [7] Kinlay S, Schwartz GG, Olsson AG, et al. Effect of atorvastatin on risk of recurrent cardiovascular events after an acute coronary syndrome associated with high soluble CD40 ligand in the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) Study. Circulation 2004;110:386–91. [8] Kinlay S, Schwartz GG, Olsson AG, et al. High-dose atorvastatin enhances the decline in inflammatory markers in patients with acute coronary syndromes in the MIRACL Study. Circulation 2003;108:1560–6. [9] Schwartz GG, Olsson AG, Ezekowitz MD, et al. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL Study: a randomized controlled trial. JAMA 2001;285:1711–8. [10] Tousoulis D, Antoniades C, Katsi V, et al. The impact of early administration of low-dose atorvastatin treatment on inflammatory process, in patients with unstable angina and low cholesterol level. Int J Cardiol 2006;109:48–52. [11] Tousoulis D, Bosinakou E, Kotsopoulou M, Antoniades C, Katsi V, Stefanadis C. Effects of early administration of atorvastatin treatment on thrombotic process in normocholesterolemic patients with unstable angina. Int J Cardiol 2006;106:333–7. [12] Spin JM, Vagelos RH. Early use of statins in acute coronary syndromes. Curr Cardiol Rep 2002;4:289–97. [13] Stefanadi E, Tousoulis D, Antoniades C, et al. Early initiation of lowdose atorvastatin treatment after an acute ST-elevated myocardial
[14] [15]
[16]
[17]
[18] [19]
[20]
[21]
303
infarction, decreases inflammatory process and prevents endothelial injury and activation. Int J Cardiol in press. Ma FX, Han ZC. Statins, nitric oxide and neovascularization. Cardiovasc Drug Rev 2005;23:281–92. Gurgun C, Ildizli M, Yavuzgil O, et al. The effects of short term statin treatment on left ventricular function and inflammatory markers in patients with chronic heart failure. Int J Cardiol 2008;123:102–7. Llevadot J, Murasawa S, Kureishi Y, et al. HMG-CoA reductase inhibitor mobilizes bone marrow-derived endothelial progenitor cells. J Clin Invest 2001;108:399–405. Walter DH, Rittig K, Bahlmann FH, et al. Statin therapy accelerates reendothelialization: a novel effect involving mobilization and incorporation of bone marrow-derived endothelial progenitor cells. Circulation 2002;105:3017–24. Endres M. Statins: potential new indications in inflammatory conditions. Atheroscler Suppl 2006;7:31–5. Landmesser U, Engberding N, Bahlmann FH, et al. Statin-induced improvement of endothelial progenitor cell mobilization, myocardial neovascularization, left ventricular function, and survival after experimental myocardial infarction requires endothelial nitric oxide synthase. Circulation 2004;110:1933–9. Thum T, Fraccarollo D, Galuppo P, et al. Bone marrow molecular alterations after myocardial infarction: impact on endothelial progenitor cells. Cardiovasc Res 2006;70:50–60. Antman EM, Hand M, Armstrong PW, et al. 2007 focused update of the ACC/AHA 2004 guidelines for the management of patients with ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2008;51:210–47.