Getting at the heart of the issue: advanced imaging and stem cell‐based therapy offer a novel approach to cardiac resynchronization

The pump function of the left ventricle (LV) is dependent on synchronous depolarization and contraction to expel blood efficiently. The propagation of the apical-to-basal ventricular contraction pattern is controlled by electrical signalling of the fibre system down the interventricular septum and woven through the free walls of the ventricular myocardium. Dyssynchronous contraction results in mechanical inefficiency, decreased external work, and reduced cardiac output. Myocardial infarction (MI) may cause wall motion abnormalities not only through disturbed electrical conduction, but also through myocardial damage and non-viable tissue. Therapy targeted at preventing adverse remodelling and improving the viability of non-contracting tissue may have the potential for great improvement in ventricular synchronization by addressing mechanical disturbances in the myocardium. Recent advances in stem cell therapy hold promise for regenerative cardiac interventions, as the use of undifferentiated stem cells delivered to the myocardium may be effective in forming functional cardiac tissue and restoring global heart function. While the potential use of such therapies has gained recent attention, the administration of stem cell therapy to ameliorate regional dyssynchrony related to MI has not been examined. In a recent issue of The Journal of Physiology, Yamada et al. (2013) investigated the effect of targeted induced pluripotent stem (iPS) cell delivery to acutely infarcted tissue on subsequent ventricular resynchronization and the prevention of organ decompensation in a murine model. Building upon previous work (Nelson et al. 2010), the investigators examined the effects of biological interventions on cardiac function following coronary ligation-induced MI. Fibroblasts or iPS cells were delivered to mapped peri-infarcted sites 30 min post-ligation. Ventricular synchrony was evaluated at longitudinal follow-up using echocardiography. Findings indicated that fibroblast delivery had a negligible impact on cardiac function at 3 months follow-up, and was associated with scarring and dyssynchrony similar to controls. However, iPS cell delivery resulted in improved regional contractility, resynchronization of ventricular wall motion, and normalization of global indices of cardiac function. Furthermore, the follow-up mortality rate at 3 months in the iPS group was 0% with no adverse effects detected. In contrast, fibroblast-treated and vehicle-treated groups suffered mortality rates of 22% and 20%, respectively, at 3 months follow-up, and presented with scarring, progressive LV dilatation and systemic heart failure. Taken together, this work provides the initial proof-of-concept suggesting that targeted iPS cell transplantation minimizes scar burden and may offer a novel strategy to preserve cardiac dynamics post-infarction through tissue repair. Previous studies have utilized echocardiography to quantify cardiac function in mice (Bauer et al. 2011). Much of this work has employed M-mode, B-mode, or Doppler imaging to assess global and, to some extent, regional function. Although these techniques characterize global ventricular function well, they are unable to adequately identify hypocontractile regions such as those in peri-infarcted areas post-MI, and are unsuitable for the high-resolution mapping required for targeted cell delivery. Speckle-tracking echocardiography is a novel technique that is less susceptible to the influence of tethering and translation. By dividing the myocardium into segments and calculating segmental values for strain indices, speckle-tracking is superior in identifying hypocontractile regions and is well suited to identify disparate wall motion. In the present study, speckle-tracking allowed for the discrimination between infarcted and peri-infarcted tissue by examining strain patterns across myocardial segments and identifying segments with reduced contractility or systolic stretch. This information was used to map the region of initial insult and the transitional zone, allowing targeted epicardial injection of iPS cells to optimize regenerative efforts. Furthermore, quantification of intraventricular time-to-peak strain showed reduced variability in iPS- compared with fibroblast-treated groups at follow-up, demonstrating the ability of iPS cells to mitigate adverse remodelling and mediate biological resynchronization in vivo. Therefore, the use of speckle-tracking strain was a strength of the current study, allowing for not only the mapping of peri-infarcted regions and evaluation of ventricular synchrony, but also quantitative longitudinal evaluation of interventional success. Speckle-tracking echocardiography has clinical applications beyond MI, having been used to identify infarcts in non-ST-elevated acute coronary events, and to evaluate the effectiveness of reperfusion therapy; more broadly, it may be employed for the early detection of subclinical cardiomyopathies and arrhythmias, and their progression. Although cardiac magnetic resonance imaging may be considered the gold standard for mapping and quantification of regional function with superior spatial resolution, it is limited by its availability, cost, complex image acquisition, and time-consuming analysis. In contrast, high-definition echocardiography is more readily available, and may be used efficiently at the bedside or in the operating theatre. The use of this sophisticated technique will be invaluable in translating stem cell-based regenerative strategies from pre-clinical to clinical populations, allowing for the assessment of myocardial function post-MI, infarct mapping to guide targeted therapy, and tracking of responses to both conventional (intracoronary infusion) and unconventional (direct endocardial injection) therapies. The ability to bioengineer iPS cells from somatic tissue sources harbours tremendous potential in the field of cardiovascular regenerative medicine. As Yamada et al. (2013) demonstrated in their proof-of-concept study, transplantation of iPS cells into the epicentre of infarcted myocardial regions allows for the formation of functional cardiac tissue and offers a regenerative strategy that addresses the mechanical substrate thought to underlie cardiac dyssynchrony and organ decompensation post-MI, which is the non-viable tissue itself. However, despite the promise that this regenerative strategy holds in the treatment of cardiac dyssynchrony post-infarction, a number of challenges inherent to stem cell-based therapies, including optimization of the stem cell source, dose, and delivery methods, must be resolved to unlock the full clinical potential of this innovative therapeutic platform. Specifically, it is unclear whether cell viability and retention will be undermined in the long-term with reprogramming. While there was no evidence of uncontrolled cell growth or mortality at 3 month follow-up in the present study, these findings cannot be extrapolated to give a long-term prognosis beyond the controlled pre-clinical setting. As such, the response of regenerative tissue to physiological stressors (i.e. exercise), ischaemic events, inflammation, immunological threats, as well as in the context of age-related and degenerative disease models (Nussbaum et al. 2007), needs to be assessed, as this may modify the efficacy of this interventional strategy and limit the translational potential of stem cell-based therapies to clinical populations. In the present study, the regenerative capacity of iPS cells was assessed in the context of an acute model of MI. However, the growth factor and chemokine milieux of the acutely injured and chronically remodelled myocardia significantly differ (Penn et al. 2011), raising questions about the ability of stem cell-based regenerative strategies to reverse maladaptive remodelling, ensure synchronization, and improve contractility of the dysfunctional myocardium. As a result, it is possible that there may be a window post-infarction beyond which stem cell-based interventions are not viable or feasible, which may ultimately be related to the duration of MI and subsequent reperfusion injury; however, the association between the degree of dysfunction and the success of stem cell-based regenerative therapies has yet to be established. Therefore, the criteria and therapeutic goals for use of stem cell-based interventions, whether it is prevention or treatment of maladaptive remodelling, need to be considered. While these unresolved challenges will need to be addressed to optimize the clinical potential of iPS and other stem cell-based therapies, the findings of the present study are cause for optimism. Despite the promise that iPS cell therapy holds for improving global ventricular function, the direct translation of this therapy to device-based cardiac resynchronization therapy (CRT) is limited. Specifically, device-based CRT strategies are typically applied late in the remodelling phase, with the absence of significant reversal of maladaptive ventricular remodelling in one-third of CRT patients owing to a number of other factors, including asynchronous electrical activation, mechanical dyssynchrony and LV lead position (Adelstein et al. 2011). Although the current study provides evidence for the potential benefit afforded by regenerative strategies in an acute model of MI, the translational potential of this therapy in the context of CRT remains unknown. As such, future work should aim to directly assess if targeted stem cell-based strategies can reverse mechanical dyssynchrony in the chronically remodelled heart following MI. The work of Yamada et al. (2013) provides the initial, proof-of-concept for the targeted use of iPS cells as a regenerative strategy for myocardial infarction, which may prevent progressive regional myocardial dyssynchrony. Using an integrative approach, including the use of high-resolution imaging and targeted transplantation of iPS cells, the authors have demonstrated that delivery of iPS cells to the site of infarction within an acute window of time is a viable concept to prevent adverse remodelling and preserve myocardial function. This therapy may be of future value in high-risk cardiac patients, offering an individualized approach whereby stem cells could be implanted rapidly following MI in an effort to salvage myocardial function. None declared. We would like to thank Dr Susanna Mak for her helpful insights and review of this manuscript.

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