Translating Myocardial Remuscularization.

Clinically relevant remuscularization of the failing human heart remains unachieved to date. Proof-of-concept studies in small and large animal models provide compelling evidence as to the principle feasibility of myocardial remuscularization with human cardiomyocyte grafts. Clinical trials suggest myocardial protection and preservation by cell therapeutics. The mechanisms underlying the reported therapeutic effects remain under debate, but likely include the release of protective factors (growth factors, noncoding RNA) and modulation of the disease-related inflammatory response. Further studies are needed to define the paracrine milieu hypothesis and unleash its full therapeutic potential, aiming at delaying or preventing disease progression in patients with acute and subacute myocardial injury. The implantation of cardiomyocyte grafts follows a different strategy, namely remuscularization by integration of exogenously produced cardiomyocytes. Patients with chronically scarred myocardium presenting clinically with end-stage heart failure are the primary target. The suggested plug-and-play mechanism of direct cardiac remuscularization seems straight forward, but similar as for the paracrine milieu hypothesis there is a clear need for a better understanding of how, when, and where to integrate exogenous cardiomyocytes into the failing heart to achieve optimal results. Moreover, the path toward clinical application as offthe-shelf cardiomyocyte allograft therapeutics is less defined as for point-of-care autograft formulations and small chemical or biological compounds. A challenge to direct cardiac remuscularization was for many years the limited availability of bona fide cardiomyocytes. Cardiac biopsies can be used to harvest proliferative mesenchymal cells with progenitor cell properties, but without the capacity to spontaneously convert/transdifferentiate into terminally differentiated cardiomyocytes at a therapeutically relevant scale. Induced conversion of fibroblasts into cardiomyocytes was recently established and is presently being advanced for direct targeting of cardiac scar fibroblasts in vivo. Fine-tuning to enhance the robustness of the directed conversion process, to enable clinically relevant scales, and— especially if developed for direct in vivo applications—to target explicitly scar fibroblasts is required before translational impact can be assessed. Similarly, applicability for ex vivo cardiomyocyte production and allocation to myocardial remuscularization remains to be evaluated. Inotropic support by remuscularization in patients with end-stage heart failure was first attempted by skeletal myoblast implantation. This was in part based on the observation that myoblasts convert into contractile myotubes with the propensity for electromechanical integration into cardiomyocyte syncytia. Despite some early enthusiasm, this approach was abandoned because of arrhythmias and no palpable efficacy. With the introduction of human embryonic and induced pluripotent stem cells, protocols to direct their myocardial differentiation (reviewed by Burridge et al), and scalable cardiomyocyte production in bioreactors important milestones toward clinical translation were met (Figure). Today, cardiomyocytes can be generated from stocks of well-characterized pluripotent stem cells according to standard operating procedures with therapeutic product validation according to current good manufacturing practice for cryopreservation and retrieval as an off-the-shelf allograft therapy. Although in principle feasible, autologous therapies via induced pluripotent stem cells do not seem to be a viable option for patients with end-stage heart failure and limited survival (patients listed for heart transplantation or patients on mechanical circulatory support either as bridge-to-transplant or destination therapy), because of procedural challenges associated with the development of an individual cell therapy; these include (1) time-consuming production with limited possibilities for process acceleration, (2) the need for individual product validation according to regulatory demands, (3) a considerable chance for product failure or at least variation, and (4) high costs for individualized therapy targeting a large patient population. Despite the availability of bona fide human cardiomyocytes and tissue-engineered human myocardium for applications in heart remuscularization and unequivocal evidence for the propensity of cardiomyocyte grafts to electromechanically integrate, it remains a challenge to achieve long-term graft retention and to establish solid evidence in support of the hypothesis that cardiomyocyte implantation has more to offer than classical pharmacological and device therapy alone or in combination in end-stage heart failure. This caveat has to be viewed, however, in light of the potential chances, the undisputed mechanism of action (enhanced contractility by electromechanical integration of cardiomyocyte grafts), and Translating Myocardial Remuscularization