Improving myocardial viability: clinical implications for the use of bone marrow-derived stem cell infusion after acute myocardial infarction

Corresponding Author:

Jerome Roncalli
Department of Cardiology A, CIC-Biothérapies, INSERM U1048
Rangueil University Hospital, Toulouse, France
Tel: +33 561 323 635
Fax: +33 561 322 246
E-mail: roncalli.j@chu-toulouse.fr

Abstract

Keywords

acute myocardial infarction, bone marrow-derived stem cells, left ventricular ejection fraction, myocardial viability

The treatment of acute myocardial infarction (AMI) has evolved substantially over the past three decades, after an improvement in the mortality rate of AMI due to thrombolytics [1,2] and primary percutaneous intervention for coronary reperfusion [3]. Less than a decade ago, initial reports on the clinical application of mononucleated bone marrow-derived stem cells (BMCs) in patients with AMI opened up a new era of regenerative cardiology and brought with it great enthusiasm [4]. Since then, numerous clinical trials have been carried out, with the aim of assessing the efficacy and safety of bone marrow stem cell therapy. Randomized Phase II trials have demonstrated contradictory results, but finally a significant improvement in cardiac function assessed by left ventricular ejection fraction (LVEF) after cell therapy was highlighted in meta-analyses [5–7]. Some of the discrepancies between some trials may be explained by differences in cell isolation and storage procedures [8]. Nevertheless, there was some evidence to suggest that BMC-based therapy is effective at improving LVEF in certain subpopulations, such as patients with large AMI and decreased LVEF [7,9]. Improvement of LVEF is of clinical relevance, since an increased LVEF achieved with cell transplantation is within an intriguingly similar range compared with established therapeutic strategies [10]. Several mechanisms of action have been suggested, but improvement in myocardial viability had never been assessed before the Bone Marrow in Acute Myocardial Infarction (BONAMI) trial [11].

Myocardial stunning following reperfusion after AMI

Patients with a substantial amount of dysfunctional but viable myocardium are likely to benefit from myocardial revascularization and may demonstrate improvement in regional and global contractile function, symptoms, exercise capacity and long-term prognosis [12]. Nonviable myocardium will usually not resume contractile function after standard revascularization strategies [13]. After rapid reperfusion following acute myocardial infarction, the heart suffers from an alteration of myocardial viability defined as hibernation or a phenomenon termed myocardial stunning [14]. Myocardial stunning is characterized by a prolonged mechanical dysfunction after coronary reperfusion, despite resumption of normal perfusion by coronary angioplasty. Stunning appears to result from alterations in contractile proteins and the generation of reactive oxygen species that impair contractility or by disturbed cellular calcium homeostasis [15]. Specifically, ischemia may lead to decreased responsiveness of the contractile protein machinery to calcium, calcium overload and excitation/contraction uncoupling because of sarcoplasmic reticulum dysfunction. Both mechanisms may not be mutually exclusive and may represent components of the same process. In humans, the return to functional recovery may require days to weeks [15]. Hence, diagnostic methods to distinguish myocardial viability from necrosis are particularly relevant for clinical investigation and patient management in patients with acute and severe left ventricular (LV) dysfunction after revascularization. For example, the ability to distinguish hibernation from stunning could potentially elucidate the prevalence, natural history and relative importance of these two entities in the development of heart failure associated with ischemic heart disease.

Methods for myocardial viability assessment

One major limitation for detailed myocardial viability is the lack of a true gold standard definition. Moreover, histopathological verification of viability in patients is impossible. Thus, the ideal methodology to assess myocardial viability would provide accurate noninvasive measurements of perfusion, metabolism and cellular membrane integrity, in addition to systolic and diastolic function, with sufficient spatial and temporal resolution for a detailed reconstruction of the entire LV. Increasingly, attempts at assessing multiple aspects of viable myocardium are being made with various noninvasive technologies.

“In several animal studies, bone marrow cell transplantation has induced angiogenesis, prevented ventricular dilatation and improved function.”

Noninvasive assessment of myocardial viability has been studied using multiple imaging techniques, including single-photon emission computed tomography (SPECT), MRI, PET and dobutamine stress echocardiography. These techniques have been extensively evaluated for assessment of viability and prediction of clinical outcome after myocardial revascularization. SPECT imaging uses various tracers to assess perfusion and cell integrity as hallmarks of viability. This technique is widely used and available in most centers, with a reproducible quantitative assessment of viability expressed as a percentage of tracer intake for each myocardial segment. Cardiac MRI is now considered as a gold standard for the evaluation of cardiac function and LV remodeling owing to its high reproducibility and low inter-/intra- observer variability. When imaging at the acute phase of MI, cardiac MRI and SPECT imaging do not evaluate the same pathophysiological pattern. Detection of MI by MRI requires first myocardial gadolinium wash-in when injected. Accordingly, MRI results reflect the integrity of microvasculature. Then, contrast is based on washout differences of contrast agent between injured myocardium and remote regions. It relates to an increased distribution volume related to increased extracellular space and cell membrane rupture (necrosis). Thus, post-gadolinium cardiac MRI, which is performed most commonly 10 min after injection in reperfused AMI, demonstrates a mix of necrosis and myocardial edema (i.e., myocardial damage) while thallium-201 SPECT impairment demonstrates, from a metabolic point of view, the absence of cellular viability (i.e., myocardial salvage). The increase in extracellular space (resulting from necrosis but also myocardial edema) leads to an overestimation of MI size by MRI in the order of 10–15% in the acute phase. Both experimental and clinical studies indeed demonstrated the decrease of myocardial late enhancement a few weeks after MI, and once edema disappeared replacement fibrosis becomes the only mechanism responsible for an increase of extracellular space [16].

Implication of bone marrow-derived stem cells in the recovery of myocardial viability

Alteration in myocardial viability is a logical target for cell therapy to accelerate recovery of contractile left ventricular function. However, so far, little is known about the mechanisms of action when autologous bone marrow-derived stem cells are targeted to the infarct zone after reperfusion. In several animal studies, bone marrow cell transplantation has induced angiogenesis, prevented ventricular dilatation and improved function [17]. In clinical studies, modern noninvasive bio-imaging techniques are of paramount importance to evaluate the true extent of myocardial restoration and justify the concurrent use of stem cells. Rest-redistribution thallium 201-SPECT was chosen in the BONAMI trial to evaluate changes in myocardial viability since it provides a good estimate of myocyte cellular membrane integrity. Indeed, 34% (16 out of 47) of patients treated with autologous BMC had improved myocardial viability compared with the control group (16%; 7 out of 43), although this was only statistically significant in multivariate analysis. Importantly, although MRI is sensitive enough to detect myocardial fibrosis, and superior to SPECT in case of small infarct with subendocardial necrosis [18,19], patients who were included in the BONAMI trial suffered from an inaugural large infarction with severe decrease of EF (mean EF of ~36% as demonstrated by radionuclide angiography) and a large scar extent of approximately 40%, as assessed by MRI. In this case of large MI, MRI may not be superior to SPECT in evaluating myocardial viability [18,19].

The commonly hypothesized mechanisms for cell therapy efficacy, namely myocardial regeneration, salvage and local perfusion, should lead to improvement of myocardial viability as a primary event that would later translate into an improvement of LVEF and/or limitation of LV remodeling. In the BONAMI trial there was no significant improvement of LVEF 3 months after cell therapy, although myocardial viability was enhanced. There is a complex relation between viability and contractility after STEMI, with contractile dysfunction related not only to the balance between necrosis and viability, but also to the extent of metabolic damage in viable myocytes [20]. Hence, recovery of contractility in some but not all regions with preserved metabolic viability might be observed [21]. Interestingly, the strong tendency towards improvement in myocardial viability observed in the BONAMI study can be placed alongside the restoration of microvascular function observed in the REPAIR-AMI cardiac cell therapy clinical trial [9] study and the probable importance of restoring a microvascular function [22]. More than restoration of blood flow; BMCs may act against myocardial stunning and thus accelerate the recovery of cardiac function. Nevertheless, the relationship between cell therapy and cardiac recovery needs further preclinical investigations and large clinical trials.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

References

1. Bonnefoy E, Steg PG, Boutitie F et al.:Comparison of primary angioplasty andpre-hospital fibrinolysis in acute myocardialinfarction (CAPTIM) trial: a 5‑year followup.Eur. Heart J. 30(13), 1598–1606 (2009).
2. Roncalli J, Brunelle F, Galinier M et al.:Pre-hospital fibrinolysis followedby angioplasty or primary angioplasty inacute myocardial infarction: the long-termclinical outcome. J. Thromb. Thrombolysis15(3), 181–188 (2003).
3. 3Grines CL, Browne KF, Marco J et al.:A comparison of immediate angioplasty withthrombolytic therapy for acute myocardialinfarction. The Primary Angioplasty inMyocardial Infarction Study Group. N. Engl.J. Med. 328(10), 673–679 (1993).
4. Strauer BE, Brehm M, Zeus T et al.:Repair of infarcted myocardium byautologous intracoronary mononuclear bonemarrow cell transplantation in humans. Circulation 106(15), 1913–1918 (2002).
5. Abdel-Latif A, Bolli R, Tleyjeh IM et al.:Adult bone marrow-derived cells for cardiacrepair: a systematic review and meta-analysis.Arch. Intern. Med. 167(10), 989–997(2007).
6. Lipinski MJ, Biondi-Zoccai GG, Abbate Aet al.: Impact of intracoronary cell therapy onleft ventricular function in the setting ofacute myocardial infarction: a collaborativesystematic review and meta-analysisofcontrolled clinical trials. J. Am. Coll. Cardiol.50(18), 1761–1767 (2007).
7. Martin-Rendon E, Brunskill SJ, Hyde CJ,Stanworth SJ, Mathur A, Watt SM:Autologous bone marrow stem cells to treatacute myocardial infarction: a systematicreview. Eur. Heart J. 29(15), 1807–1818(2008).
8. Seeger FH, Tonn T, Krzossok N, Zeiher AM,Dimmeler S: Cell isolation procedures matter:a comparison of different isolation protocolsof bone marrow mononuclear cells used forcell therapy in patients with acute myocardialinfarction. Eur. Heart J. 28(6), 766–772(2007).
9. Schachinger V, Erbs S, Elsasser A et al.:Intracoronary bone marrow-derived progenitorcells in acute myocardial infarction. N. Engl.J. Med. 355(12), 1210–1221 (2006).
10. Reffelmann T, Konemann S, Kloner RA:Promise of blood- and bone marrow-derivedstem cell transplantation for functional cardiacrepair: putting it in perspective with existingtherapy. J. Am. Coll. Cardiol. 53(4), 305–308(2009).
11. Roncalli J, Mouquet F, Piot C et al.:Intracoronary autologous mononucleated bonemarrow cell infusion for acute myocardialinfarction: results of the randomizedmulticenter BONAMI trial. Eur. Heart J. DOI:10.1093/eurheartj/ehq455 (2010) (Epub aheadof print).
12. Allman KC, Shaw LJ, Hachamovitch R,Udelson JE: Myocardial viability testing andimpact of revascularization on prognosis inpatients with coronary artery disease and leftventricular dysfunction: a meta-analysis.J. Am. Coll. Cardiol. 39(7), 1151–1158(2002).
13. Wu KC, Lima JA: Noninvasive imaging ofmyocardial viability: current techniques andfuture developments. Circ. Res. 93(12),1146–1158 (2003).
14. Braunwald E, Kloner RA: The stunnedmyocardium: prolonged, postischemicventricular dysfunction. Circulation 66(6),1146–1149 (1982).
15. Bolli R, Marban E: Molecular and cellularmechanisms of myocardial stunning. Physiol.Rev. 79(2), 609–634 (1999).
16. Fieno DS, Hillenbrand HB, Rehwald WGet al.: Infarct resorption, compensatoryhypertrophy, and differing patterns ofventricular remodeling following myocardialinfarctions of varying size. J. Am. Coll. Cardiol.43(11), 2124–2131 (2004).
17. Flynn A, O’Brien T: Stem cell therapy forcardiac disease. Expert Opin. Biol. Ther. 11(2),177–187 (2010).
18. Wagner A, Mahrholdt H, Holly TA et al.:Contrast-enhanced MRI and routine singlephoton emission computed tomography(SPECT) perfusion imaging for detection ofsubendocardial myocardial infarcts: animaging study. Lancet 361(9355), 374–379(2003).
19. Ibrahim T, Bulow HP, Hackl T et al.:Diagnostic value of contrast-enhancedmagnetic resonance imaging and single-photonemission computed tomography for detection ofmyocardial necrosis early after acute myocardialinfarction. J. Am. Coll. Cardiol. 49(2), 208–216(2007).
20. Beygui F, Le Feuvre C, Helft G, Maunoury C,Metzger JP: Myocardial viability, coronary flowreserve, and in-hospital predictors of laterecovery of contractility following successfulprimary stenting for acute myocardialinfarction. Heart 89(2), 179–183 (2003).
21. Panza JA, Dilsizian V, Laurienzo JM,Curiel RV, Katsiyiannis PT: Relation betweenthallium uptake and contractile response todobutamine. Implications regardingmyocardial viability in patients with chroniccoronary artery disease and left ventriculardysfunction. Circulation 91(4), 990–998(1995).
22. Werner C, Bohm M, Friedrich EB: Progenitorcell therapy and myocardial infarction: theimportance of microvascular function. Nat.Clin. Pract. Cardiovasc. Med. 5(2), 78–79(2008).