4.3 / IAGS 2019
Session 1: Coronary Session 2: STEMI
Stem Cell Therapy for Heart Failure Post AMI
Problem Presenter: Mike Mooney
Statement of problem or issue
The heart is the least regenerative organ in the body. With an infarction, injured myocardial tissue has little chance of regenerating, and is replaced by scar. This disturbs the normal mechanical functioning of the heart, and can leave it operating in a reduced capacity, possibly leading to clinical heart failure. Stem cells, which are uncommitted precursor cells, have the theoretic potential to differentiate into myocytes in the injury zones, recovering some or all of the normal mechanical function and preventing development of heart failure. Early clinical trials were positive (BOOST [Lancet 2004;364:141–48]; REPAIR-AMI [N Engl J Med 2006;355:1210-1221]), but more recent trials have been less encouraging (MHIF Pilot Trial [Am Heart J 2010;160:428-34; Late-TIME Trial [JAMA 2012;308:2380-2389]; SWISS-AMI [Circulation 2013;127:1968-1979]. The poor uptake (engraftment) and short retention of the administered stem cells has been a major barrier.
Gaps in knowledge
An improved understanding of uncommitted cell types that could differentiate into myocytes, and/or provide appropriate paracrine signals, might advance the therapeutic options. Unraveling the biological pathways of these processes will require more research. Uptake and prolonged residence of any cells in the injured myocardium has been problematic. Providing a stable background matrix for cellular retention in the appropriate myocardial sites is one possibility. Another knowledge gap that must be bridged is the observed arrhythmogenic potential of the stem cell colonies within the myocardium. These new cells do not have the same electrodynamic properties of surrounding myocardium.
Possible solutions and future directions
New cell types are undergoing evaluation as potential candidates for therapy. These new cell lines include bone-marrow-derived and adipose-derived mesenchymal stem cells (MSCs), cardiac-derived stem cells (c-kit+), embryonic stem cells, skin-derived or blood-derived induced pleuripotent stem cells (iPS), mesoblast cells, and cardiopoietic progenitor cells. In addition, new research is being conducted on the extracellular matrix (ECM) components that can help anchor the stem cells in the desired myocardial sites. Normal ECM is composed of families of fibrous proteins like collagen, fibronectin, laminen, proteoglycans, and others. ECM is degraded in areas of infarction and is replaced by scar, which is mostly composed of heavily cross-linked fibrillary collagen chains that may not be a suitable substrate for stem cells. Various natural and synthetic materials are being investigated as possible surrogate ECM. Alginate, derived from seaweed, is a polysaccharide that has favorable properties. Other substances include engineered collagen- and fibrin-based matrices, as well as decellularized porcine cardiac matrix hydrogels. These new advances in stem cell types and biomaterial-tissue engineering may bring about new synergies in regenerative cardiac stem cell therapy. In summary, while the concept of myocardial regeneration is attractive, the challenges remain considerable. Finally, it is important to make the distinction regarding stem cell therapy for refractory angina or peripheral arterial disease, where the goal is to improve blood flow. In contrast to myocardial regeneration, these other trials have been quite positive and are already available in selected countries.