Cardiac cell therapy: a call for action

It has been suspected since the mid-20th century that cardiomyocytes have very low powers of regeneration. In the 1990s, it was demonstrated that syngeneic neonatal skeletal myoblasts can be transplanted into necrotic myocardium and contract when stimulated electrically.1 Because of growing interest in the potential therapeutic benefits of cardiac cell therapy (CCT), the National Heart, Lung and Blood Institute (NHLBI) held a workshop on this subject in 2000. It concluded: ‘…cell transplantation is becoming recognized as a viable strategy to strengthen weak hearts and limit infarct growth’ and encouraged research in the field.2 The following year, Menasché et al.3 successfully implanted autologous skeletal myoblasts into a patient’s post infarct scarred left ventricle. Although viable and contracting, the implant became the focus of ventricular arrhythmias. Nonetheless, the workshop and single case report attracted a great deal of attention and energized the field. In 2002, Strauer et al.4 reported reduced ventricular damage with injection of autologous unfractionated mononuclear bone marrow cells into the infarct-related arteries in a small group of patients with acute myocardial infarction. Although this observation was initially confirmed in a placebo-controlled trial, these results could not be repeated by several investigators, and the preponderance of currently available evidence does not support the earlier observations. This early research on CCT, while superficially neutral, actually provided important information. It suggested that patients in the first few days following an acute myocardial infarction may not be optimal candidates for this approach and that unfractionated bone marrow mononuclear cells are not the optimal cells to use. It also demonstrated that for preclinical studies in the field to be meaningful and reproducible, they must be carried out in rigorous fashion, with prespecified protocols and statistical analyses. As a consequence, the NHLBI sponsored the development of requirements for such investigations, entitled CAESAR,5 that are now widely used. Mesenchymal stromal (bone marrow-derived) cells (MSCs) are attractive candidates for CCT because their protective actions improve left ventricular function and because they are not rejected, but they do suppress inflammation.6 They can be administered intravenously, into the coronary arteries, or by direct transendocardial injection; the latter improves cell retention. Phase II trials have demonstrated that a variety of MSCs, including cells derived from bone marrow, umbilical cord and adipose tissue, look promising. The MSC-HF trial, a phase II placebo-controlled study of bone marrow-derived MSCs in patients with ischaemic heart failure, showed a robust improvement in left ventricular function at a 12-month follow-up.7 c-kit positive cardiac cells (CPCs) have also been shown to be effective in multiple preclinical studies in four species,8 leading to the CONCERT-HF trial, a randomized, phase II, double blind, multicenter, placebo-controlled trial of bone marrow-derived MSCs, CPCs or their combination. Both CPCs alone and CPCs combined with MSCs reduced heart failure-related major adverse events in patients with chronic ischemic heart failure.9 The objective of the DREAM HF trial, a phase III placebo-controlled randomized trial of 537 patients with heart failure of ischemic or non-ischemic origin and reduced ejection fraction, was to determine whether transendocardially injected allogeneic bone marrow-derived MSCs reduce the rate of non-fatal recurrent heart failure events. While this trial did not meet its primary endpoint, it reduced significantly an important secondary composite endpoint of cardiac death, non-fatal MI or non-fatal stroke.10 In addition to these promising CCT trials on the treatment of heart failure, Henry et al.11 reported a pooled analysis of randomized trials in patients with refractory angina showing that autologous CD34+ cells released from the bone marrow and isolated from peripheral blood, reduced mortality and angina frequency and improved exercise capacity. Initially, CCT was considered analogous to organ transplantation, but with large numbers of individual cells rather than a solid organ or tissue. It was anticipated that the transplanted cells would improve cardiac function by regenerating functional cardiomyocytes. However, it was soon observed that the transplanted cells do not engraft well in the myocardium but disappear in days to a few weeks and do not differentiate into cardiomyocytes nor do they promote the formation of sufficient new myocytes to account for their efficacy.8 In 2005, Gnecchi et al.12 proposed that paracrine signalling accounts for the action of transplanted cells. It is now widely held that these cells release a variety of mediators including proangiogenic growth factors, cytokines, chemokines and extracellular vesicles; the latter include exosomes, which contain a variety of proteins including matrix metalloproteinases, bioactive lipids, mRNAs, miRNAs and mitochondria derived from their parent cells. It is now believed that one or some combination of these substances act on and enhance the function of cardiomyocytes with anti-inflammatory, anti-apoptopic and antifibrotic properties. It is believed that these biologically active substances act not only on adjacent cells (paracrine) but also at a distance through the blood stream (endocrine).8 Despite these several proposed mechanisms of action, derived largely from preclinical studies, further elucidation and identification of those that are operative clinically are needed. Multiple studies have shown that CCT is safe.13 Unfortunately, despite the encouraging results of the aforementioned Phase II clinical trials, only a few of which are mentioned above, efforts to move CCT into clinical practice seem to have fallen by the wayside. Other than the DREAM-HF trial,10 clinicaltrials.gov show only one other small phase III trial being conducted in adults. The number of phase II trials is small as well, and the few that are currently enrolling patients are variations of previous trials. With the exception of the Mesoblast Corporation (sponsor of the DREAM-HF trial10), there appears little commercial involvement in clinical CCT. There are several possible reasons for this troubling situation. One is the recent improvements in the treatment of heart failure, rapid reperfusion in acute myocardial infarction and the more effective management of patients with subacute or chronic heart failure with SGLT2 inhibitors14 and sacubitril/valsartan. However, while important, these advances do not abolish or ‘cure’ heart failure, although they may delay it. Also, the widely publicized misconduct in an important laboratory conducting preclinical research in this field may have discouraged both potential sponsors and investigators from investing resources and effort in CCT. However, it is useful to remember the adage: ‘Rome was not built in a day.’ The contemporary management of hypertension as well as of atherosclerotic vascular disease has evolved over decades and is still improving. CCT has come a long way during the past few years. I see four possible directions for the future. The first, simplest and potentially very effective, is to utilize multiple dosing, i.e. booster shots, as suggested by Bolli et al.8 The second is to move some of the exciting results of phase II trials into phase III. The third is to attempt to isolate the specific paracrine factor(s) that appear to be responsible for the benefits derived from transplanted cells, manufacture them in vitro and make them available off the shelf, i.e. provide ‘cell therapy without cells’. The fourth, and perhaps most exciting, is based on the 2012 Nobel Prize-winning research of Shinya Yamanaka, the Japanese scientist who discovered how mature cells can be reprogrammed to become pluripotent stem cells that are able to develop into all types of cells.15 Human-induced pluripotent stem cell-derived cardiomyocytes have been shown to improve ventricular function in a primate model of acute myocardial infarction.16 Two phase I trials in patients with heart failure with these cells have begun in Asia. It would be unfortunate indeed if clinical investigators are not encouraged to build on the recent substantial advances in CCT. Hence, this call for action! Conflict of interest: Research grant support through Brigham and Women’s Hospital from: AstraZeneca, Daiichi-Sankyo, Merck and Novartis; consulting for: Amgen, Boehringer-Ingelheim/Lilly, Bristol Myers Squibb (MyoKardia), Cardurion, NovoNordisk and Verve.