REVIEW For reprint orders, please contact: [email protected]
An update on primary findings and new designs in biotherapy studies for acute myocardial infarction Jerome Roncalli* ABSTRACT Treatment of acute myocardial infarction in the future should focus not only on improving acute treatment, as it has been done over the past decades, but also on secondary prevention of left ventricular dysfunction and/or progression to heart failure by preserving left ventricular shape, avoiding left ventricular remodeling and stimulating cardiac regeneration. Biotherapies with adult stem cells and bone marrow-derived endothelial cell progenitors, combined or not with biomaterials, and new drugs are under investigation and will probably be part of routine clinical practice for patients suffering from myocardial infarction in the near future. Acute myocardial infarction (AMI) is often associated with excessive and continuous damage to the extracellular matrix (ECM), infarct expansion leading to progressive wall degradation and scar thinning, left ventricular (LV) dilatation and transition to heart failure (HF) [1,2] . While selected centers have made tremendous progress in ensuring high-quality care and rapid revascularization for the treatment of patients with ST-segment elevation myocardial infarction, there remains a definite need for standardizing of pre-hospital and hospital management to shorten time to diagnosis and door to balloon worldwide. The design of optimized clinical pathways for ensuring high-quality and homogeneous early AMI diagnosis and management at a national level remains an important issue worldwide. Recently, we showed that pre-hospital thrombolysis has a role in the management of patients seen early after symptom onset in comparison/association with patients who had primary coronary intervention or elective primary coronary intervention [3,4] . This is an important issue, which is still currently being investigated to prevent cardiac arrest and large scars, limit transition to HF and improve survival rate after AMI. Thus, management of AMI has been regularly well defined and updated by the European Society of Cardiology to help physicians in routine clinical practice over the past decades [5] . However, there remain many important areas in the management of AMI that offer opportunities for future research from prevention of LV dysfunction to cardiac regeneration.
KEYWORDS
• alginates • biomaterials • cardiac regeneration • cardioprotection • mesenchymal stromal cells • CD34+ cells • left
ventricular remodeling • mononucleated cells
Mechanical/pharmacological approaches & biomaterials to limit myocardial injury & LV remodeling Reducing or minimizing myocardial injury and LV dysfunction following AMI remains a crucial goal. Several strategies are being tested, using a variety of pharmacological and nonpharmacological approaches. Although reperfusion has already demonstrated efficacy, it may have detrimental effects, including myocardial stunning, ventricular arrhythmias and microvascular dysfunction [6,7] . Accumulating evidence suggests that reperfusion may also cause irreversible myocardial injury, possibly through dysfunction of the permeability transition in the mitochondria [8] . Indeed, metabolic alterations involving calcium overload and excessive production of reactive oxygen species in the early minutes of reflow may lead to cardiomyocyte death [9] triggered by the opening of the mitochondrial *Department of Cardiology A, Clinical Center of Investigation of Biotherapies, CIC-BT 0511; CHU of Toulouse, University of Toulouse; Toulouse, France; Tel.: +33 561 323 334; Fax: +33 561 322 246; [email protected]
10.2217/FCA.14.65 © 2014 Future Medicine Ltd
Future Cardiol. (2014) 10(6), 781–788
part of
ISSN 1479-6678
781
Review Roncalli permeability transition pore. Postconditioning inhibits the opening of the mitochondrial permeability transition pore and provides powerful anti-ischemic protection [9] . Thus, local ischemic postconditioning (consisting of four cycles of 1-min inflation and 1-min deflation of the angioplasty balloon) and remote ischemic preconditioning (consisting of three cycles of 5-min inflation and 5-min deflation of an upper-arm blood-pressure cuff initiated before reperfusion) are thought to be promising cardioprotective therapies in ST-elevation myocardial infarction. However, combining this therapy strategy did not lead to a further decrease in infarct size [10] . Moreover, in our recent report [11] , we showed that infarct size reduction by mechanical ischemic postconditioning is lost when applied to patients with a TIMI 2–3 flow grade at admission. This indicates that the timing of the protective intervention with respect to the onset of reperfusion is a key factor for preventing lethal reperfusion injury in ST-elevation myocardial infarction patients. Cyclosporine A, a molecule well known for its immunosuppressive properties, has been shown to be a potent inhibitor of mitochondrial permeability transition, and several reports indicate that it can limit ischemia/reperfusion injury under experimental conditions [12] . A recent pilot study showed that the administration of cyclosporine A in patients with AMI was associated with a reduction in infarct size [13] . These data were preliminary and require confirmation in the larger ongoing CIRCUS trial [14] . Current antiremodeling therapies are clearly limited, since many ventricles continue to enlarge [15,16] with a round shape like a ‘soccer balloon’ and morbidity and mortality remain high [17] . In the field of nonpharmacological devices, recent experiments in animals have suggested that direct injection of biomaterials, such as alginate, fibrin, collagen and self-assembling peptides, into the infarct could limit LV remodeling [18–20] . It has recently been shown that a solution of calcium crosslinked alginate can be injected via a needle into the infarct, where it undergoes phase transition into hydrogel [21] . The alginate hydrogel implant provides temporary physical support to the damaged cardiac tissue by replacing some of the functions of the damaged ECM, while preventing adverse cardiac remodeling by constraining the myocardium from expanding and dysfunction after recent and old myocardial infarction in rats [20] .
782
Future Cardiol. (2014) 10(6)
In a recent study it has been shown that intracoronary (ic.) injection of an alginate biomaterial in a model of AMI with coronary reperfusion in larger animals (swine) is feasible and effective in preventing adverse cardiac remodeling [22] . The alginate biomaterial was given 4 days postAMI and follow-up was 60 days. The device aids the healing and repair phase after AMI. After ic. injection, the alginate solution disseminates through the vessels into the infarct and undergoes phase transition into a hydrogel. Both replacement of the damaged ECM in the infarcted tissue and the scaffolding effect of the alginate hydrogel provided physical support to the infarcted tissue, enhanced healing and prevented LV dilation. After 6 weeks, the liquid dissolves and is excreted from the body through the kidneys. Thus, the implant was gradually replaced by myofibroblasts and connective tissue. An increased number of myofibroblasts in the scar was considered a marker of improved healing. A Phase I, first-in-human clinical study was initiated by BioLineRx in March 2008 in Europe to evaluate the safety of 2 ml of alginate IK-5001 (BL-1040) administered via ic. injection up to 1 week after AMI in subjects at high risk for LV remodeling and HF to provide feasibility and safety data prior to initiating a pivotal clinical study. In this multicenter, openlabel, sequentially enrolled, pilot trial, safety of the device was tested in a total of 27 patients with AMI and resulted in approval for the ongoing PRESERVATION trial, which is currently designed to assess the efficiency of such a strategy on a larger population [23] . Biomaterial injection shows several advantages over current approaches of treatment of LV remodeling after AMI. The ability to deliver biomaterial into the infarct by ic. injection could revolutionize patient treatment after AMI and could prevent mechanical complications, HF and death. Cardiac cell therapies for AMI The effectiveness and safety of cell therapies to replace myocardium or minimize the consequences of myocardial injury need to be confirmed. However, during the past decade, the importance of stem cells and endothelial progenitor cells (EPCs) in cardiovascular disease prognosis and recovery has been established. Cardiovascular cell therapy has been successfully delivered by intracoronary infusion, transvascular administration or intramyocardial transplantation (endocardially or epicardially), and has been
future science group
Update on primary findings & new designs in biotherapy studies for AMI used to treat several cardiovascular diseases. The greatest clinical progress has been achieved in the setting of chronic myocardial ischemia with or without LV dysfunction and is still explored and even debated after an AMI. Pioneering cohort and Phase I uncontrolled clinical studies rapidly demonstrated the feasibility of applying bone marrow cell (BMC) therapy to the human heart [24] independently of the route of administration. Furthermore, more recent randomized, Phase II controlled trials used BMCs for treatment of acute or previous myocardial infarction, chronic ischemic HF and intractable angina. BMCs were of particular interest for early studies because they have been clinically used for more than 30 years and have a positive safety profile. Unselected BMCs were also used because the relative potency of cellular subpopulations is currently unclear, and because techniques for enriching the EPC fraction were only recently simplified. In addition, results from preclinical studies indicate that the number of EPCs available in the peripheral blood is insufficient for autologous therapy unless they are mobilized from the bone marrow by granulocyte colonystimulating factor (GCSF) and/or expanded in culture. However, selection of cells with greater regenerative potency (e.g., CD34 + cells [25]) could enable delivery of a smaller cell dose, thereby reducing the risk of adverse effects but without reducing efficiency. In the Bone Marrow Transfer to Enhance ST-elevation Infarct Regeneration (BOOST) and Reinfusion of Enriched Progenitor Cells and Infarct Remodeling in Acute Myocardial Infarction (REPAIR-AMI) trials [26] , patients (BOOST: n = 30 per treatment group; REPAIRAMI: n = 102 per treatment group) received BMCs via ic. infusion after AMI. BMC therapy was associated with improved LV function 6 (BOOST) and 4 (REPAIR-AMI) months after treatment [26–28] . At 18 months, LV function was similar between the treatment groups in the BOOST trial [29] , but significant clinical improvements were sustained for up to 12 months and 5 years in the REPAIR-AMI study [26] . These promising results were contradicted by other studies that found no significant difference in LV function with BMC therapy [30,31] . Although randomized trials reported mixed results, metaanalyses have shown a significant improvement in cardiac function assessed by LV ejection fraction (LVEF) after cell therapy. After performing the first systematic review and meta-analysis,
future science group
Review
Abdel-Latif et al. concluded that BMC therapy was safe, improved LV function and reduced scarring [32] . Some of the discrepancies between these large trials could be explained by differences in criteria for patient selection and, at least in part, by differences in the cell isolation and storage procedures [33] . Thus, other meta-analyses confirmed results showing BMC efficiency [34–36] . We recently combined data from 16 studies [37] including 1641 patients (984 receiving cell therapy and 657 controls). The absolute improvement in LVEF was greater among BMCtreated patients compared with controls (2.55% increase; 95% CI: 1.83–3.26; p < 0.001). Cell therapy significantly reduced LV volumes (LV end-diastolic volume index: 23.17 ml/m2, 95% CI: 24.86–21.47, p < 0.001; and LV end-systolic volume index: 22.60 ml/m 2, 95% CI: 23.84– 21.35, p < 0.001). Treatment benefit in terms of LVEF improvement was more pronounced in younger patients (age
An update on primary findings and new designs in biotherapy studies for acute myocardial infarction Jerome Roncalli* ABSTRACT Treatment of acute myocardial infarction in the future should focus not only on improving acute treatment, as it has been done over the past decades, but also on secondary prevention of left ventricular dysfunction and/or progression to heart failure by preserving left ventricular shape, avoiding left ventricular remodeling and stimulating cardiac regeneration. Biotherapies with adult stem cells and bone marrow-derived endothelial cell progenitors, combined or not with biomaterials, and new drugs are under investigation and will probably be part of routine clinical practice for patients suffering from myocardial infarction in the near future. Acute myocardial infarction (AMI) is often associated with excessive and continuous damage to the extracellular matrix (ECM), infarct expansion leading to progressive wall degradation and scar thinning, left ventricular (LV) dilatation and transition to heart failure (HF) [1,2] . While selected centers have made tremendous progress in ensuring high-quality care and rapid revascularization for the treatment of patients with ST-segment elevation myocardial infarction, there remains a definite need for standardizing of pre-hospital and hospital management to shorten time to diagnosis and door to balloon worldwide. The design of optimized clinical pathways for ensuring high-quality and homogeneous early AMI diagnosis and management at a national level remains an important issue worldwide. Recently, we showed that pre-hospital thrombolysis has a role in the management of patients seen early after symptom onset in comparison/association with patients who had primary coronary intervention or elective primary coronary intervention [3,4] . This is an important issue, which is still currently being investigated to prevent cardiac arrest and large scars, limit transition to HF and improve survival rate after AMI. Thus, management of AMI has been regularly well defined and updated by the European Society of Cardiology to help physicians in routine clinical practice over the past decades [5] . However, there remain many important areas in the management of AMI that offer opportunities for future research from prevention of LV dysfunction to cardiac regeneration.
KEYWORDS
• alginates • biomaterials • cardiac regeneration • cardioprotection • mesenchymal stromal cells • CD34+ cells • left
ventricular remodeling • mononucleated cells
Mechanical/pharmacological approaches & biomaterials to limit myocardial injury & LV remodeling Reducing or minimizing myocardial injury and LV dysfunction following AMI remains a crucial goal. Several strategies are being tested, using a variety of pharmacological and nonpharmacological approaches. Although reperfusion has already demonstrated efficacy, it may have detrimental effects, including myocardial stunning, ventricular arrhythmias and microvascular dysfunction [6,7] . Accumulating evidence suggests that reperfusion may also cause irreversible myocardial injury, possibly through dysfunction of the permeability transition in the mitochondria [8] . Indeed, metabolic alterations involving calcium overload and excessive production of reactive oxygen species in the early minutes of reflow may lead to cardiomyocyte death [9] triggered by the opening of the mitochondrial *Department of Cardiology A, Clinical Center of Investigation of Biotherapies, CIC-BT 0511; CHU of Toulouse, University of Toulouse; Toulouse, France; Tel.: +33 561 323 334; Fax: +33 561 322 246; [email protected]
10.2217/FCA.14.65 © 2014 Future Medicine Ltd
Future Cardiol. (2014) 10(6), 781–788
part of
ISSN 1479-6678
781
Review Roncalli permeability transition pore. Postconditioning inhibits the opening of the mitochondrial permeability transition pore and provides powerful anti-ischemic protection [9] . Thus, local ischemic postconditioning (consisting of four cycles of 1-min inflation and 1-min deflation of the angioplasty balloon) and remote ischemic preconditioning (consisting of three cycles of 5-min inflation and 5-min deflation of an upper-arm blood-pressure cuff initiated before reperfusion) are thought to be promising cardioprotective therapies in ST-elevation myocardial infarction. However, combining this therapy strategy did not lead to a further decrease in infarct size [10] . Moreover, in our recent report [11] , we showed that infarct size reduction by mechanical ischemic postconditioning is lost when applied to patients with a TIMI 2–3 flow grade at admission. This indicates that the timing of the protective intervention with respect to the onset of reperfusion is a key factor for preventing lethal reperfusion injury in ST-elevation myocardial infarction patients. Cyclosporine A, a molecule well known for its immunosuppressive properties, has been shown to be a potent inhibitor of mitochondrial permeability transition, and several reports indicate that it can limit ischemia/reperfusion injury under experimental conditions [12] . A recent pilot study showed that the administration of cyclosporine A in patients with AMI was associated with a reduction in infarct size [13] . These data were preliminary and require confirmation in the larger ongoing CIRCUS trial [14] . Current antiremodeling therapies are clearly limited, since many ventricles continue to enlarge [15,16] with a round shape like a ‘soccer balloon’ and morbidity and mortality remain high [17] . In the field of nonpharmacological devices, recent experiments in animals have suggested that direct injection of biomaterials, such as alginate, fibrin, collagen and self-assembling peptides, into the infarct could limit LV remodeling [18–20] . It has recently been shown that a solution of calcium crosslinked alginate can be injected via a needle into the infarct, where it undergoes phase transition into hydrogel [21] . The alginate hydrogel implant provides temporary physical support to the damaged cardiac tissue by replacing some of the functions of the damaged ECM, while preventing adverse cardiac remodeling by constraining the myocardium from expanding and dysfunction after recent and old myocardial infarction in rats [20] .
782
Future Cardiol. (2014) 10(6)
In a recent study it has been shown that intracoronary (ic.) injection of an alginate biomaterial in a model of AMI with coronary reperfusion in larger animals (swine) is feasible and effective in preventing adverse cardiac remodeling [22] . The alginate biomaterial was given 4 days postAMI and follow-up was 60 days. The device aids the healing and repair phase after AMI. After ic. injection, the alginate solution disseminates through the vessels into the infarct and undergoes phase transition into a hydrogel. Both replacement of the damaged ECM in the infarcted tissue and the scaffolding effect of the alginate hydrogel provided physical support to the infarcted tissue, enhanced healing and prevented LV dilation. After 6 weeks, the liquid dissolves and is excreted from the body through the kidneys. Thus, the implant was gradually replaced by myofibroblasts and connective tissue. An increased number of myofibroblasts in the scar was considered a marker of improved healing. A Phase I, first-in-human clinical study was initiated by BioLineRx in March 2008 in Europe to evaluate the safety of 2 ml of alginate IK-5001 (BL-1040) administered via ic. injection up to 1 week after AMI in subjects at high risk for LV remodeling and HF to provide feasibility and safety data prior to initiating a pivotal clinical study. In this multicenter, openlabel, sequentially enrolled, pilot trial, safety of the device was tested in a total of 27 patients with AMI and resulted in approval for the ongoing PRESERVATION trial, which is currently designed to assess the efficiency of such a strategy on a larger population [23] . Biomaterial injection shows several advantages over current approaches of treatment of LV remodeling after AMI. The ability to deliver biomaterial into the infarct by ic. injection could revolutionize patient treatment after AMI and could prevent mechanical complications, HF and death. Cardiac cell therapies for AMI The effectiveness and safety of cell therapies to replace myocardium or minimize the consequences of myocardial injury need to be confirmed. However, during the past decade, the importance of stem cells and endothelial progenitor cells (EPCs) in cardiovascular disease prognosis and recovery has been established. Cardiovascular cell therapy has been successfully delivered by intracoronary infusion, transvascular administration or intramyocardial transplantation (endocardially or epicardially), and has been
future science group
Update on primary findings & new designs in biotherapy studies for AMI used to treat several cardiovascular diseases. The greatest clinical progress has been achieved in the setting of chronic myocardial ischemia with or without LV dysfunction and is still explored and even debated after an AMI. Pioneering cohort and Phase I uncontrolled clinical studies rapidly demonstrated the feasibility of applying bone marrow cell (BMC) therapy to the human heart [24] independently of the route of administration. Furthermore, more recent randomized, Phase II controlled trials used BMCs for treatment of acute or previous myocardial infarction, chronic ischemic HF and intractable angina. BMCs were of particular interest for early studies because they have been clinically used for more than 30 years and have a positive safety profile. Unselected BMCs were also used because the relative potency of cellular subpopulations is currently unclear, and because techniques for enriching the EPC fraction were only recently simplified. In addition, results from preclinical studies indicate that the number of EPCs available in the peripheral blood is insufficient for autologous therapy unless they are mobilized from the bone marrow by granulocyte colonystimulating factor (GCSF) and/or expanded in culture. However, selection of cells with greater regenerative potency (e.g., CD34 + cells [25]) could enable delivery of a smaller cell dose, thereby reducing the risk of adverse effects but without reducing efficiency. In the Bone Marrow Transfer to Enhance ST-elevation Infarct Regeneration (BOOST) and Reinfusion of Enriched Progenitor Cells and Infarct Remodeling in Acute Myocardial Infarction (REPAIR-AMI) trials [26] , patients (BOOST: n = 30 per treatment group; REPAIRAMI: n = 102 per treatment group) received BMCs via ic. infusion after AMI. BMC therapy was associated with improved LV function 6 (BOOST) and 4 (REPAIR-AMI) months after treatment [26–28] . At 18 months, LV function was similar between the treatment groups in the BOOST trial [29] , but significant clinical improvements were sustained for up to 12 months and 5 years in the REPAIR-AMI study [26] . These promising results were contradicted by other studies that found no significant difference in LV function with BMC therapy [30,31] . Although randomized trials reported mixed results, metaanalyses have shown a significant improvement in cardiac function assessed by LV ejection fraction (LVEF) after cell therapy. After performing the first systematic review and meta-analysis,
future science group
Review
Abdel-Latif et al. concluded that BMC therapy was safe, improved LV function and reduced scarring [32] . Some of the discrepancies between these large trials could be explained by differences in criteria for patient selection and, at least in part, by differences in the cell isolation and storage procedures [33] . Thus, other meta-analyses confirmed results showing BMC efficiency [34–36] . We recently combined data from 16 studies [37] including 1641 patients (984 receiving cell therapy and 657 controls). The absolute improvement in LVEF was greater among BMCtreated patients compared with controls (2.55% increase; 95% CI: 1.83–3.26; p < 0.001). Cell therapy significantly reduced LV volumes (LV end-diastolic volume index: 23.17 ml/m2, 95% CI: 24.86–21.47, p < 0.001; and LV end-systolic volume index: 22.60 ml/m 2, 95% CI: 23.84– 21.35, p < 0.001). Treatment benefit in terms of LVEF improvement was more pronounced in younger patients (age
