Author + information
- aCardiology Service, Germans Trias i Pujol University Hospital, Badalona, Spain
- bDepartment of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain
- cICREC Research Program, Health Science Research Institute Germans Trias i Pujol, Badalona, Spain
- dCenter of Regenerative Medicine in Barcelona, Barcelona, Spain
- ↵∗Reprint requests and correspondence:
Dr. Antoni Bayés-Genís, Heart Institute, Germans Trias i Pujol University Hospital, ICREC (Heart Failure and Cardiac Regeneration) Research Program, Crta. Canyet, s/n, 08916 Badalona, Barcelona, Spain.
Cardiac tissue engineering is becoming a prime destination on the road map for translational medicine, often referred to as bench-to-bedside research (1,2). It has been 20 years since the first cardiac tissue engineering papers were published; now more than 700 papers are added each year under the key words “cardiac tissue engineering.” Despite this abundant and growing body of literature, translation from pre-clinical experimentation to clinical trials has been rare. In a review published in 2014, the majority of in vivo experiments were still performed in murine models, which are valuable as proof-of-principle but not valid for clinical translation (2). Large mammals, particularly swine, are the preferred pre-clinical models for testing cardiac tissue engineering approaches given the similarity of their coronary anatomy, myocardial physiology, and size to that of humans (3). In addition, advanced noninvasive imaging techniques, particularly cardiac magnetic resonance, are better surrogates for cardiac function remodeling or function restoration than conventional transthoracic ultrasound (4).
To date, the number of cardiac engineering approaches that have translated into the clinic has been low. Pioneers in this translational process must be commended. Chachques et al. (5) reported the results of the MAGNUM (Myocardial Assistance by Grafting a New Bioartificial Upgraded Myocardium) trial in 2008. This was a phase I-II trial of the application of collagen matrix seeded with bone marrow cells onto left ventricular (LV) post-ischemic myocardial scars in 10 patients with an indication for coronary artery bypass graft surgery. The cell-seeded collagen matrix increased scar thickness and limited ventricular remodeling. More recently, also in France, a clinical trial was reported that involved the use of human embryonic stem cell–derived cardiac progenitors delivered in a fibrin hydrogel to the epicardial surface during open heart surgery (6). In this issue of the Journal, Rao et al. (7) report the results of PRESERVATION I (Prevention of Remodeling of the Ventricle and Congestive Heart Failure After Acute Myocardial Infarction), a randomized, double-blind, controlled trial that evaluated the safety and effectiveness of an injectable bioabsorbable alginate, which the authors referred to as bioabsorbable cardiac matrix (BCM), for the prevention of ventricular remodeling after large ST-segment elevation myocardial infarction (STEMI).
Biomaterials represent a cornerstone of the tissue engineering paradigm and are emerging as an alternative therapy to facilitate self-repair, reverse or attenuate adverse remodeling, and ultimately achieve long-term functional stabilization and improved heart function. Alginate, an algae-derived polysaccharide, has been widely used in tissue engineering and regeneration because of its relatively low cost, mild and ionotropic gelation process, nonthrombogenicity, and structural resemblance to the extracellular matrix (8). The injectable BCM used in this study can be delivered by intracoronary injection as a solution; when delivered to the infarct-related arteries, it is able to traverse the leaky coronary vessels to the infarcted tissue (9,10). The therapeutic effects of BCM on myocardial repair have been tested in murine and swine myocardial infarction models (9,10). Serial echocardiography studies have been performed in both of these models, which showed that intracoronary injection of partially cross-linked alginate solution into the infarcted heart is feasible, safe, and effective (10).
These beneficial pre-clinical studies appear to support proceeding to clinical translation, although the results of PRESERVATION I failed to support the earlier findings. Intracoronary delivery of BCM to subjects who had successful percutaneous coronary intervention with stent placement after STEMI failed to reduce adverse LV remodeling or cardiac clinical events at 6-month follow-up.
What went wrong? First, was the deployed volume enough? The majority of patients received the protocol-specified dose of 4 ml. Leor et al. (10) tested incremental volumes of biomaterial (1, 2, and 4 ml) and showed that the beneficial effects of alginate hydrogel are dose dependent. The size of the STEMI in the PRESERVATION trial was much larger than that generated in the pig model, and it probably required a larger volume of BCM to be effective. Second, is the preclinical model correct? In the swine model of acute infarction and LV remodeling, the myocardium is not protected against adverse remodeling with clinically available drugs, namely, beta blockers, angiotensin-converting enzyme inhibitors, and mineraloreceptor antagonists, which were given to the participants of PRESERVATION I. Third, was the assessment of the primary endpoint, LV end-diastolic volume index measured by transthoracic echocardiography, optimal? The LV end-diastolic volume index changed from baseline to 6 months with BCM treatment or saline (14.1 ± 28.9 ml/m2 and 11.7 ± 26.9 ml/m2, respectively; p = 0.49). This huge standard deviation, twice the size of the mean change values, points toward a serious limitation of the selected imaging technique. Cardiac magnetic resonance has emerged as the standard reference modality for the assessment of LV dimensions, global LV function, and myocardial mass in translational research.
Finally, was the route of delivery problematic? Another clinical study using a different form of alginate hydrogel used intramyocardial injection as the delivery route in heart failure patients during scheduled coronary artery bypass graft surgery (11). This was a safety study, and LV volumes decreased substantially in all patients 3 months after treatment. More recently, the AUGMENT-HF (Algisyl-LVR as a Method of Left Ventricular Augmentation for Heart Failure) trial found that intramyocardial deployment of alginate hydrogel through a limited left thoracotomy approach in patients with advanced chronic heart failure was more effective at improving exercise capacity and symptoms than standard medical therapy alone (12).
Cardiac tissue engineering using alginate biomaterial is on the road to clinical translation. Indeed, 3 injectable alginate implants have reached the clinical investigation phase, which confirms the potential of alginate-based approaches for myocardial repair and regeneration. Nevertheless, further insights into the mechanisms, route of delivery, timing, and clinical setting are mandatory to minimize translational failure. Safety issues must also be acknowledged. Rao et al. (7) reported differences in stent thrombosis between the 2 arms (3.1% vs. 0% for BCM and saline, respectively). Although not statistically significant, the finding certainly deserves further research to better understand whether this is related to intracoronary alginate delivery after successful STEMI percutaneous coronary intervention or just play of chance. Pre-clinical fine-tuning has the potential to limit conflicting results from clinical trials; otherwise, inconsistencies might ignite scientific and social prejudice against this novel discipline and promote disillusionment as, once again, basic science gets lost in translation. In the 1990s, we got lost in the clinical translation of gene therapy, and in the early 2000s, we got lost in the search for the best stem cell story to translate. Let’s learn from our previous mistakes for the sake of our patients’ health.
↵∗ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
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