Cardiac cell repair therapy: a clinical perspective

Abstract

From bone marrow transplants 5 decades ago to the most recent stem cell-derived organ transplants, regenerative medicine is increasingly recognized as an emerging core component of modern practice. In cardiovascular medicine, innovation in stem cell biology has created curative solutions for the treatment of both ischemic and nonischemic cardiomyopathy. Multiple cell-based platforms have been developed, harnessing the regenerative potential of various natural and bioengineered sources. Clinical experience from the first 1000 patients (approximately) who have received stem cell therapy worldwide indicates a favorable safety profile with modest improvement in cardiac function and structural remodeling in the setting of acute myocardial infarction or chronic heart failure. Further investigation is required before early adoption and is ongoing. Broader application in practice will require continuous scientific advances to match each patient with the most effective reparative phenotype, while ensuring optimal cell delivery, dosing, and timing of intervention. An interdisciplinary effort across the scientific and clinical community within academia, biotechnology, and government will drive the successful realization of this next generation of therapeutic agents for the "broken" heart.

FIGURE 1.

Advantages and disadvantages of different cell types isolated from different sources used both clinically and experimentally. EPC = endothelial progenitor cell; HSC = hematopoietic stem cell; MSC = mesenchymal stem cell.

FIGURE 2.

Methods of cell delivery for cardiac implantation. A, intravenous administration; B, intracoronary infusion using a balloon catheter after restoration of arterial patency; C, transepicardial injection via thoracotomy into the border zone of the infarct; D, transendocardial approach using electromechanical voltage mapping to define tissue viability; and E, intravenous injection into the coronary veins via the coronary sinus, enabling cell delivery into myocardial areas subserved by occluded coronary vessels.

FIGURE 3.

Concept of the universality of benefit noted in animal and clinical studies, with the exception of some recent randomized trials that have reported discordant results. The 6700-fold variation in dose among different studies is obtained from reference . LV = left ventricular; LVEF = LV ejection fraction; MI = myocardial infarction. From Indian Heart J.

FIGURE 4.

Schematic illustrating potentially beneficial mechanisms underlying cell repair or cell regenerative therapy. Prevailing concepts have shifted away from direct cellular effects resulting in transdifferentiation into cardiomyocytes and toward the cytokine-paracrine hypothesis. The underlying rationale is that transplant of cells or factors developed in culture media enhances angiogenesis, curbs inflammation, improves metabolic modulation, and reduces apoptosis, resulting in increased reparative and cardioprotective responses as opposed to regeneration per se. Adapted from Indian Heart J.

FIGURE 5.

Meta-analysis of 10 randomized controlled trials enrolling 698 participants comparing patients diagnosed as having acute myocardial infarction who were treated with autologous stem-progenitor cells with those who were not. A random-effects model was used, and marked heterogeneity was observed between trials. Nonetheless, a consistent pattern suggests that bone marrow stem cell treatment improves short-term left ventricular ejection fraction (LVEF), with similar trends for left ventricular end-systolic and end-diastolic volumes, infarct size, and regional cardiac wall motion (not shown). A positive correlation was also found between cell dose infused and the effect on LVEF measured with magnetic resonance imaging. Conclusions could not be drawn on clinical outcomes such as mortality because of insufficient events. ASTAMI = Autologous Stem Cell Transplantation in Acute Myocardial Infarction; BOOST = Bone Marrow Transfer to Enhance ST-Elevation Infarct Regeneration; CI = confidence interval; MAGIC = Myoblast Autologous Grafting in Ischemic Cardiomyopathy; REPAIR-AMI = Intracoronary Progenitor Cells in Acute Myocardial Infarction; TCT-STAMI = Emergent Transcatheter Transplantation of Stem Cells for Treatment of Acute Myocardial Infarction. From J Am Coll Cardiol, with permission.

FIGURE 6.

The overall objective of ongoing and future clinical trials is to obtain a better understanding of current cells before moving on to the modification of cells and evaluation of new cell types. LV = left ventricular; MI = myocardial infarction.

FIGURE 7.

This illustrates the hierarchical classification of end points in clinical trials. CHF = chronic heart failure; LV = left ventricular. Asterisks indicate end points of current clinical trials. From Nat Clin Pract Cardiovasc Med, with permission.