Extending Flaps Lifts an Infarcted Heart Toward Repair
Authors: Gianni Angelini, Massimo Caputo, Paolo Madeddu
Journal: Molecular Therapy (2015)

Normal hearts comprise 2 × 109 myocytes, but this number may be doubled in excessively hypertrophied hearts. After a heart attack caused by blockage of one of the arteries that supply the heart, approximately 20% or more of cardiomyocytes are acutely and irreversibly lost in the ischemic area. However, the damage is not limited to the acute interruption of blood flow. Reperfusion of the ischemic territory can cause additional damage due to a burst of toxic reactive oxygen species. Moreover, additional cardiomyocytes are lost in the peri-infarct area during the subacute phase, leading to extension of the infarcted area. The ensuing remodeling response, which consists of cardiomyocyte hypertrophy and collagen accumulation, is insufficient to compensate for the massive cell loss, thus leading to scar expansion, ventricular chamber dilation, and failure. In this issue of Molecular Therapy, an elegant preclinical study by Kainuma et al.1Kainuma S Miyagawa S Pearson J Chen YC Saito A et al.Cell sheet therapy with omentopexy promotes arteriogenesis and improves coronary circulation physiology in failing heart.Mol Ther. 2015; 23: 374-386Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar documents that a combinatory tissue-engineering strategy can prevent the tragic sequelae of a heart attack. Two weeks after inducing permanent occlusion of the main coronary artery of rats, the authors randomized the animals into four groups to be implanted with a five-layered skeletal myoblast cell sheet to cover both infarct and border areas, an omental flap that was pulled from the peritoneal space to the pleural cavity onto epicardium in the ischemic area using a transdiaphragmatic approach or a skeletal myoblast cell sheet covered with an omental flap (combined group), or to receive a sham operation (control group). The results of the 28-day follow-up study indicate that the combination approach improves donor-cell retention (the Achilles’ heel of current cell therapy), amplifies angiogenesis at the capillary and arteriole levels, attenuates cardiac hypertrophy and fibrosis, and sustains cardiac function, as documented by assessment of contractile, pressure, and volumetric indexes. Moreover, using imaging technologies such as serial 13N-ammonia positron-emission tomography testing and postmortem synchrotron-based microangiography, Kainuma and colleagues show better global coronary flow reserve in the combined group (attributed mainly to improvement in the basal left ventricle) and increased vascularization in resistance arterial vessels along with better dilatory responses to endothelium-dependent agents. The latter phenomenon was sustained by the creation of robust vascular communications between the omental and native coronary arteries. At the molecular level, the most remarkable result was the increased expression of genes related to angiogenesis and vascular stabilization. Seminal work by Menasché has fueled much interest in skeletal myoblasts as ideal cells for cardiac repair, in light of their autologous origin, in vitro scalability, and high resistance to ischemia.2Menasché P Skeletal myoblasts and cardiac repair.J Mol Cell Cardiol. 2008; 45: 545-553Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar Extensive preclinical testing consistently showed that skeletal myoblasts were able to preserve postinfarct left ventricular function and limit adverse remodeling. However, skeletal myoblasts may cause electrical abnormalities in the recipient heart through mechanisms such as reentry, enhanced automaticity, and triggered activity. The increased arrhythmogenic risk reported by the first clinical study of autologous skeletal myoblast implantation3Menasché P Alfieri O Janssens S McKenna W Reichenspurner H Trinquart L et al.The myoblast autologous grafting in ischemic cardiomyopathy (MAGIC) trial: first randomized placebo-controlled study of myoblast transplantation.Circulation. 2008; 117: 1189-1200Crossref PubMed Scopus (764) Google Scholar has led to the cautionary use of defibrillator devices in subsequent clinical trials, although recent reports describe a lower incidence of ventricular arrhythmia.4Dib N Michler RE Pagani FD Wright S Kereiakes DJ Lengerich R et al.Safety and feasibility of autologous myoblast transplantation in patients with ischemic cardiomyopathy: four-year follow-up.Circulation. 2005; 112: 1748-1755Crossref PubMed Scopus (282) Google Scholar,5Siminiak T Burchardt P Kurpisz M Postinfarction heart failure: surgical and trans-coronary-venous transplantation of autologous myoblasts.Nat Clin Pract Cardiovasc Med. 2006; 3 (suppl. 1): S46-S51Crossref PubMed Scopus (14) Google Scholar Long-term follow-up of the MAGIC study confirms improvement of left-ventricle volumes in the high-dosage cell treatment group with no additional arrhythmogenic incidents.6Brickwedel J Gulbins H Reichenspurner H Long-term follow-up after autologous skeletal myoblast transplantation in ischaemic heart disease.Interact Cardiovasc Thorac Surg. 2014; 18: 61-66Crossref PubMed Scopus (27) Google Scholar The final results of a phase IIa, randomized, open-label trial to evaluate the percutaneous intramyocardial transplantation of autologous skeletal myoblasts in patients with congestive heart failure (the SEISMIC trial) indicate that the treatment is safe and may provide symptomatic relief, although no significant effect was detected on global ejection fraction.7Duckers HJ Houtgraaf J Hehrlein C Schofer J Waltenberger J Gershlick A et al.Final results of a phase IIa, randomised, open-label trial to evaluate the percutaneous intramyocardial transplantation of autologous skeletal myoblasts in congestive heart failure patients: the SEISMIC trial.EuroIntervention. 2011; 6: 805-812Crossref PubMed Scopus (89) Google Scholar However, another study showed that percutaneous injection of intramyocardial skeletal myoblasts in ischemic cardiomyopathy had no sustained positive effect on resting global or regional ventricular function at four-year follow-up. Moreover, the procedure was, again, associated with a higher risk of developing serious arrhythmias.8Veltman CE Soliman OI Geleijnse ML Vletter WB Smits PC ten Cate FJ et al.Four-year followup of treatment with intramyocardial skeletal myoblasts injection inpatients with ischaemic cardiomyopathy.Eur Heart J. 2008; 29: 1386-1396Crossref PubMed Scopus (54) Google Scholar As highlighted by Kainuma et al.,1Kainuma S Miyagawa S Pearson J Chen YC Saito A et al.Cell sheet therapy with omentopexy promotes arteriogenesis and improves coronary circulation physiology in failing heart.Mol Ther. 2015; 23: 374-386Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar the therapeutic potential of skeletal myoblasts could be undermined by their short-term retention in a hostile ischemic environment, exacerbated by the loss of contact between cells that are injected as a suspension. In this regard, the use of a multilayered sheet and the superimposed benefit of perfusion provided by the omental flap can synergistically enhance the healing capacity of myoblast therapy. Interestingly, in a preclinical study in rats with coronary artery ligation, the cell sheet technique enhanced not only the therapeutic efficacy but also the safety (fewer arrhythmogenic events) of myoblast-based therapy, compared with intramyocardial implantation of dispersed cells.9Narita T Shintani Y Ikebe C Kaneko M Harada N Tshuma N et al.The use of cell-sheet technique eliminates arrhythmogenicity of skeletal myoblast-based therapy to the heart with enhanced therapeutic effects.Int J Cardiol. 2013; 168: 261-269Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar It is therefore important to verify whether the application of a myoblast sheet together with an omental flap reduces the arrhythmogenic risk further, by improving perfusion of the area at risk, which is a major source of electric instability. The use of omentum in cardiac surgery and models of myocardial infarction has significant antecedents. The omental flap is used extensively to deal with deep sternal wound infection because placement of the flap between the sternal edges and around the heart triggers neoangiogenesis and subsequently a healing process that can combat the infection itself. The flap was proposed as long ago as 1955 by Beck and Leighninger10Beck CS Leighninger DS Scientific basis for the surgical treatment of coronary artery disease.J Am Med Assoc. 1955; 159: 1264-1271Crossref PubMed Scopus (67) Google Scholar as a potential treatment for patients with coronary artery disease at a time when coronary artery surgery did not exist. In animal models, Zhang and colleagues11Zhang C Hou J Zheng S Zheng Z Hu S Vascularized atrial tissue patch cardiomyoplasty with omentopexy improves cardiac performance after myocardial infarction.Ann Thorac Surg. 2011; 92: 1435-1443Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar used either a patch of left atrium or omentum or a composite of both (omentum on top of atrium) over a three-week-old infarct in a rat. The composite patch was most successful in contrasting the increase in left-ventricular volume at end diastole and end systole and supporting ejection fraction and reparative angiogenesis. The same authors showed that omentum sutured over artificial extracellular matrix containing mesenchymal stem cells decreased left-ventricular size and improves left-ventricular function, whereas omentum alone did not.12Zhou Q Zhou JY Zheng Z Zhang H Hu SS A novel vascularized patch enhances cell survival and modifies ventricular remodeling in a rat myocardial infarction model.J Thorac Cardiovasc Surg. 2010; 140: 1388-1396 (e1–3)Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar Kainuma et al.1Kainuma S Miyagawa S Pearson J Chen YC Saito A et al.Cell sheet therapy with omentopexy promotes arteriogenesis and improves coronary circulation physiology in failing heart.Mol Ther. 2015; 23: 374-386Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar suggest that improvement of perfusion by the omental flap is a determinant mechanism, and that the myoblast sheet acts as a bridge to link the omental vessels to intramyocardial coronary arteries. Mechanical elements may also have contributed to the observed effects on contractility and establishment of a robust vascularization. Whereas angiogenesis is induced mainly by hypoxia and results in new capillaries, arteriogenesis—which was predominantly observed here—is induced by physical forces, i.e., fluid shear stress. Moreover, wrapping the heart with both cell sheet and omentum may synergistically induce a mechanical stiffening of the infarct wall, thereby halting the scar expansion, as suggested in a modeling study by Wall and colleagues using intramyocardial injection of extracellular matrix.13Wall ST Walker JC Healy KE Ratcliffe MB Guccione JM Theoretical impact of the injection of material into the myocardium: a finite element model simulation.Circulation. 2006; 114: 2627-2635Crossref PubMed Scopus (269) Google Scholar Monocytes/macrophages are important mediators of arteriogenesis, and the application of external surfaces to the epicardium might have augmented the recruitment of circulating cells to the area at risk. This possibility should be tested in future studies using the composite approach to improve postischemic recovery. Furthermore, the epicardium contains stem cells,14Bollini S Vieira JM Howard S Dubè KN Balmer GM Smart N et al.Re-activated adult epicardial progenitor cells are a heterogeneous population molecularly distinct from their embryonic counterparts.Stem Cells Dev. 2014; 23: 1719-1730Crossref PubMed Scopus (62) Google Scholar which could be activated by the epicardial superimposition of cell sheet and omentum. The creation of a favorable angiogenic environment may induce epicardial stem cells to differentiate and migrate, thereby contributing to bridge the external circulation with coronary vessels.15Xiang FL Liu Y Lu X Jones DL Feng Q Cardiac-specific overexpression of human stem cell factor promotes epicardial activation and arteriogenesis after myocardial infarction.Circ Heart Fail. 2014; 7: 831-842Crossref PubMed Scopus (20) Google Scholar With respect to the possible clinical exploitations, the gastroepiploic artery has been used as an arterial conduit to revascularize the posterolateral wall of the myocardium in patients with coronary artery disease. It is normally harvested with a small pedicle of omentum and tunneled through the diaphragm into the posterior mediastinum.16Suma H Gastroepiploic artery graft in coronary artery bypass grafting.Ann Cardiothorac Surg. 2013; 2: 493-498PubMed Google Scholar The simple application of an omental flap without actual coronary revascularization has very limited clinical applicability and has not been used in clinical practice. Furthermore, as the authors point out, the application of an omental flap in association with thoracotomy for myoblast implantation is a complex procedure that may not be well tolerated by patients with subacute myocardial infarction. It seems more feasible to enhance the reparative activity of the myoblast sheet using concurrent reperfusion through classic coronary artery bypass graft surgery. In conclusion, Kainuma and colleagues highlight the potential of hybrid solutions of tissue engineering that on the one hand enhance stem cell engraftment and on the other hand exploit stem cells to bridge the heart with the external circulation. This combination approach could lift the infarcted heart from the risk of chronic decompensation and failure. This work was supported by grants from the British Heart Foundation and the National Institute for Health Research Bristol Cardiovascular Biomedical Research Unit.