Hippokratia 2012, 16, 4: 292-293
Anastasiadis K, Antonitsis P
Cardiothoracic Department, AHEPA University Hospital, Thessaloniki, Greece
Keywords: heart failure, assist device, stem cells, cell therapy
Correspoding author: Polychronis Antonitsis, Sakellaridi 25, 542 48, Thessaloniki, Greece, tel: +302310329729, fax: +302310004814, e-mail: firstname.lastname@example.org
Over the past two decades, cardiovascular medicine has witnessed substantial progress in the field of understanding the molecular pathogenesis of disease, genetic causes, as well as the design of more efficacious therapeutic interventions1. These advances have resulted in the dramatic reduction in the mortality of heart disease. However, both the prevalence and incidence of heart failure remain persistently high, posing new challenges and opportunities for prevention, diagnosis, and management.
Defined as the inability of the heart, as a mechanical pump, to meet the peripheral metabolic demands, this syndrome has many complex pathophysiological interactions. Progression to end-stage heart failure ominously increases morbidity and decreases life-span.
In the current issue of the journal we present preliminary results of the first series of patients with severe ischemic cardiomyopathy managed with a combined strategy of coronary bypass grafting and intramyocardial administration of autologous bone marrow stem cells in pre-defined territories of hibernating myocardium2. Encouraging results from this pilot study regarding the safety and efficacy of the procedure in terms of improvement in left ventricular systolic function and reperfusion evidenced in areas considered non-viable on preoperative evaluation prompted us to integrate this combined approach in our routine surgical practice.
In end-stage disease of ischemic or non-ischemic aetiology when no option for a surgical or electrophysiological management is anticipated, heart transplantation is considered the treatment of choice. However, this strategy is severely limited in many countries, including Greece, due to a shortage of suitable donor hearts, need for lifelong immunosuppression and financial restrictions. Long-term mechanical circulatory support is an increasingly realistic “off-the-shelf” alternative to cardiac transplantation and an effective solution for those rendered ineligible through common heart failure comorbidities3. Publications about first-generation left ventricular assist devices (LVAD) reported substantial incidences of complications, most commonly device failure, infection and thromboembolism4. In the past ten years, blood pump technology has improved markedly following the revelation that pulse pressure is not a fundamental requirement in the human circulation. Second- and third-generation rotary blood pumps are smaller and more patient-friendly than first-generation pulsatile LVADs. Favorable clinical results observed with contemporary devices led to the widespread application of mechanical support in end-stage heart failure patients worldwide.
Though implantation of an LVAD as destination therapy provides symptomatic relief through mechanical unloading, it does not lead to recovery of native cardiac function. Anecdotal clinical experience indicates that LVAD patients who manifest improvement in native left ventricular function have few adverse events, better exercise capacity and prolonged survival4. Advances in technology move towards miniaturization of the pump design and implantation through minimal invasive or even percutaneous procedures. In any case, failing left ventricular function is simply substituted with a device without removing the causative insult or restoring cell number. We consider that a true “fourth-generation” device should aim not only in mechanical ventricular assist but also in ventricular restoration at the cellular level through implementation of cellular transplantation5. Ibrahim et al recently argued that LVAD and stem cell therapy have synergistic properties based on shared mechanistic actions6. Mechanical off-loading create a favorable environment promoting homing and engraftment of transplanted stem cells, while at the same time both therapeutic modalities modulate synergistically the neurohormonal cascade, decrease cytokine expression, prevent pathological remodeling and reduce apoptosis.
Our group in a recent publication detected reperfusion and tissue viability at the site of stem cells injection which was considered non-viable in all previous preoperative and postoperative scans in a patient with ischemic cardiomyopathy managed with LVAD implantation and autologous bone marrow stem cells leading to a net reduction in the estimated infarct size7. From experimental work, autologous bone marrow cells are known to stimulate angiogenesis and attenuate remodeling of the extracellular matrix8. These cells do not transdifferentiate into cardiomyocytes but exert paracrine effects to stimulate vasculogenesis and angiogenesis9.
Currently the most promising cell population to repopulate ischemic myocardium is the cardiac resident stem cell which has proliferative potential and can be isolated using endocardial biopsy and the cardiosphere technique10. These cells are unique in their ability to secrete large amounts of all growth factors including angiopoietin-II, bFGF, HGF, IGF-I, SDF-I and VEGF. However, data from in vivo and in vitro experiments also suggest that mesenchymal stem cell therapy has beneficial effects on the survival of existing myocardium, promotion of neovascularisation and modulation of remodeling of the extracellular matrix8. Allogeneic mesenchymal stem cells are currently undergoing investigation in phase II clinical trials. Clearly, the main advantage of this approach is that the functional variability of autologous cells is alleviated by preparing a master bank of validated fully tested clinical-grade cells from which a working bank is established and then allows a well-qualified product to be readily available. Thus, an off-the-shelf hybrid therapeutic strategy that combines mechanical circulatory support with cellular therapy already seems to exist for a patient with end-stage cardiac failure due to ischemic cardiomyopathy. It remains to be further elucidated if this contemporary holistic approach (cells and pumps) in end-stage ischemic heart failure provide a realistic alternative to heart transplantation allowing scarce donor hearts to be used for more complex cardiac defects.
Disclosures: The authors disclose that there is no conflict of interest
1. Benjamin IJ. Targeting endoglin, an auxiliary transforming growth factor β coreceptor, to prevent fibrosis and heart failure. Circulation. 2012; 125: 2689-2691.
2. Antonitsis P, Anastasiadis K, Koliakos G, Vaitsopoulou C, Kouzi-Koliakou K, Doumas A, et al. Intramyocardial implantation of autologous bone marrow-derived stem cells combined with coronary artery bypass grafting in patients with ischemic cardiomyopathy: a pilot study. Hippokratia. 2012; 16: 366-370.
3. Westaby S. Advanced heart failure–an “off-the-shelf” solution? Lancet. 2008; 371: 1898-1900.
4. Westaby S, Siegenthaler M, Beyersdorf F Massetti M, Pepper J, Khayat A, et al. Destination therapy with a rotary blood pump and novel power delivery. Eur J Cardiothorac Surg. 2010; 37: 350-356.
5. Anastasiadis K, Antonitsis P, Argiriadou H, Koliakos G, Doumas A, Khayat A, et al. Hybrid approach of ventricular assist device and autologous bone marrow stem cells implantation in end-stage ischemic heart failure enhances myocardial reperfusion. J Transl Med. 2011; 9: 12.
6. Ibrahim M, Rao C, Athanasiou T, Yacoub MH, Terracciano CM. Myocardial unloading and cell therapy have a synergistic role in the recovery and regeneration of the failing heart. Eur J Cardiothorac Surg. 2012; 42: 312-318.
7. Anastasiadis K, Antonitsis P, Doumas A, Koliakos G, Argiriadou H, Vaitsopoulou C, et al. Stem cells transplantation combined with long-term mechanical circulatory support enhances myocardial viability in end-stage ischemic cardiomyopathy. Int J Cardiol. 2012; 155: e51-e53.
8. Li TS, Cheng K, Mallaisas K, Smith RR, Zhang Y, Sun B, et al. Direct comparison of different stem cell types and subpopulations reveals superior paracrine potency and myocardial repair efficacy with cardiosphere-derived cells. J Am Coll Cardiol. 2012; 59: 942-953.
9. Kinnaird T, Stabile E, Burnett MS, Shou M, Lee CW, Barr S, et al. Local delivery of marrow-derived stromal cells augments collateral perfusion through paracrine mechanisms. Circulation. 2004; 109: 1543-1549.
10. Smith RF, Barile L, Cho HC, Leppo MK, Hare JM, Messina E, et al. Regenerative potential of cardiosphere-derived cells expanded from percutaneous endomyocardial biopsy specimens. Circulation. 2007; 115: 896-908.