Strategies and Challenges to Myocardial Replacement Therapy

Abstract

Cardiovascular diseases account for the majority of deaths globally and are a significant drain on economic resources. Although heart transplants and left-ventricle assist devices are the solution for some, the best chance for many patients who suffer because of a myocardial infarction, heart failure, or a congenital heart disease may be cell-based regenerative therapies. Such therapies can be divided into two categories: the application of a cell suspension and the implantation of an in vitro engineered tissue construct to the damaged area of the heart. Both strategies have their advantages and challenges, and in this review, we discuss the current state of the art in myocardial regeneration, the challenges to success, and the future direction of the field.

Significance: This article outlines the advantages and limitations of the cell injection and patch approaches to cardiac regenerative therapy. If the field is to move forward, some fundamental questions require answers, including the limitations to the use of animal models for human cell-transplantation studies; the best way to measure success in terms of functional improvements, histological integration, electrical coupling, and arrhythmias; and where the cells should be applied for maximal benefit-the epicardium or the myocardium.

Figure 1.

Host-graft electrical coupling in animal hearts transplanted with hESC-CMs. (A): Rat. (Aa): Merged image indicating location of fluorescently labeled graft. (Ab): Electrical activation mapping at 4 Hz (240 bpm) shows slight conduction delay at graft site. (Ac–Ad): Isochronal electrical activation maps without (Ac) and with (Ad) fluorescent image overlay to indicate graft location. Maps show the interval (in ms) between the stimulus pulse and the local fluorescence increase. A slight conduction delay is evident at the graft site. Reproduced from [61] with permission. (B): Guinea pig. (Ba): Calcium mapping of a cryoinjured heart at 3 Hz (180 bpm). Top: Traces of fluorescent intensity versus time for grafts located in the border zone (1, blue) or cryoinjury zone (2, red) relative to host ECG (black) indicate coupling. Bottom: Calcium isochronal activation map showing the interval (in ms) between the stimulus pulse and the local fluorescence increase. Graft in border zone (1) shows uniform rapid activation, whereas graft in cryoinjury zone (2) shows gradual activation from edge to edge. (Bb): Calcium mapping of uninjured heart at 3 Hz (180 bpm). Top: Trace of fluorescent intensity versus time for graft relative to host ECG indicates coupling. Bottom: Calcium isochronal activation map for graft shows rapid uniform activation. Reproduced from [62] with permission. (C): Pig. (Ca, Cb): Electrical activation maps of the junctional (left) and new ventricular ectopic (right) rhythms shown from the anteroposterior (Ca) and left lateral (Cb) view. These images show that the earliest electrical activation (red) during the junctional rhythm was shifted to the graft area during the ventricular ectopic rhythm. Reproduced from [64] with permission. (D): Nonhuman primate. (Da): Heart diagram denoting regions shown in (Db–Dd). (Db): Image of fluorescently labeled graft sites denoted by the red and blue rectangles. (Dc): Graft during diastole. (Dd): Graft during systole. (De–Dh): Calcium mapping at different rates for the graft sites indicated in (Db). Traces of fluorescence intensity versus time relative to host ECG indicate coupling. Reproduced from [6] with permission. Abbreviations: AU, arbitrary units; Fl, fluorescence.

Figure 2.

Cardiac regenerative therapy options. (A): The wall of each heart chamber is comprised of three layers: endocardium, myocardium, and epicardium. Reproduced from [92] with permission. (B): Various injection locations for cardiac cell injection therapy. (C): Various cardiac patch strategies and epicardial patch placement. (B, C): Reproduced from [93] with permission. Abbreviations: AV, aortic valve, MV, mitral valve, PV, pulmonary valve, TV, tricuspid valve.