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Options for Stem Cell Delivery in Cardiology
A version of this article was originally published in CellR4. 2014; 2(1): e707, available online at https://www.cellr4.org/article/707
Regenerative medicine for ischemic heart disease and congestive heart failure has been the
subject of significant research efforts over the past decade. Data from animal studies and clinical trials in humans suggests that the introduction of stem cells and/or specific genes into the heart can improve outcomes. However, results have been mixed. Sanz-Ruiz and colleagues postulated the reasons for this variability as 1) a lack of standardization and optimization of cell isolation and delivery protocols; 2) a lack of a universally accepted nomenclature and imprecise use of terminology; and 3) a large number of stem cell types under investigation in different clinical settings.1 This summary focuses on the delivery methods for stem cell therapy to the heart and the conditions for which stem cells are under current investigation.
Coronary heart disease remains the number-one cause of death in the United States, despite a reduction in mortality of approximately 30% in the last decade. Congestive heart failure, either of ischemic or non-ischemic etiology, remains the number-one hospital diagnosis-related group (DRG), a leading cause of death, and economic drain on the economy. Significant advances in the treatment of coronary artery disease (CAD) have occurred through new medications, new percutaneous techniques such as balloon angioplasty and intracoronary stent placement, as well as improvements in surgical revascularization (CABG). The treatment of congestive heart failure has also experienced advances in the form of new medications, left ventricular assist devices, and cardiac transplantation. Most of the success in revascularization has occurred at the level of the epicardial coronary arteries. Unfortunately, significant ischemia remains in a large number of patients due to inadequate perfusion at the small arteriolar level or in segments of the heart for which there is no option for epicardial reperfusion. Medications have not completely resolved this problem.
Studies evaluating the effects of stem cells in heart disease have focused on four basic mechanisms: 1) Neo-angiogenesis (new blood vessel formation); 2) Neo-myogenesis (new cardiac muscle formation); 3) Myocardial salvage (in patients with acute myocardial infarction) through stem cells’ effects on reducing ischemia and hypoxic damage, reducing inflammation, and reducing the effects of oxidative stress (reperfusion injury); and 4) Reduction in adverse re-modeling which occurs as a result of stem cells’ effects on the previously mentioned mechanisms. These effects occur at the small arteriolar or cellular level. The primary mechanisms of action are the paracrine-based mechanisms of angiogenesis, anti-inflammation, and anti-apoptosis. Myocyte regeneration, while documented, does not play a significant clinical role in the results. Further research is required and is ongoing.
The goal of stem cell therapy in any organ system is to deliver the best cells to the best place at the best time for the best duration to achieve the best patient outcomes. For physicians, better outcomes are measured using metrics such as ejection fraction, mixed venous oxygen saturation (MVO2), objective measures of ischemia, and mortality. Patients view outcomes in more subjective terms, such as relief of chest pain, reduction in shortness of breath, improved exercise tolerance, as well as living longer. Regardless of the metrics, the potential of stem cell therapy for achieving patient outcome improvement remains enticing and is nearing reality.
Stem cells reside in a number of tissues throughout the body. Embryonic stem cells, harvested from embryos in the 3- to 5-day-old blastocyst stage, possess the ability to differentiate into any of the over 200 tissue types of the body, but their use remains restricted in many countries, including the U.S., for ethical reasons. Adult stem cells, which are able to differentiate into fewer tissue types, are present in many locations. By far, stem cells originating from bone marrow have undergone the most study. Both bone marrow mononuclear cells and mesenchymal cells have been used in research studies. Adipose-derived stem cells have also received significant attention and are the focus of ongoing research. Other tissue sources of adult stem cells, such as umbilical cord, placenta and the heart itself, are also under investigation. It is not clear if the source of the stem cell makes a difference in the outcome of the patient. Studies are also ongoing to evaluate the feasibility of allogeneic vs. autologous stem cells, which would offer the advantage of “off-the-shelf” availability and potentially offer a solution to age-related drawbacks of some stem cells in older patients.
The primary targets of stem cell therapy for cardiac disease are those caused by ischemia. Studies in patients with acute and chronic ischemic heart disease, with or without congestive heart failure (CHF), are ongoing. A small number of studies on the use of stem cells in patients with CHF of non-ischemic etiology have also occurred, but the study sizes have been small and the results mixed.
Options for stem cell delivery are based on the different underlying pathophysiologic mechanisms and the necessity of avoiding complications. The primary conditions for the use of stem cells under current study in cardiology include both acute and chronic ischemic heart disease, and CHF, both of ischemic and non-ischemic etiology. Complications include those experienced with catheter-based interventions via the femoral artery, as well as cardiac arrhythmias and cardiac tamponade for intra-myocardial injections. Venous approaches through peripheral veins or centrally through the femoral vein carry less risk of a vascular complication.
Early attempts at intravenous delivery of stem cells were found to be low risk, but without benefit. The cells were cleared through the first-pass effect of the lung and did not reach or remain in the heart in a large enough number or of significant duration to stimulate repair.
Intracoronary injection is the preferred method of delivery for patients with acute myocardial infarction. The risk of arrhythmia is avoided by avoiding direct contact with the myocardium, but the dwell time for cells introduced into the arterial system is limited. There appears to be a paracrine-based homing mechanism for stem cells for the first 5-7 days following an acute myocardial infarction (MI). This would suggest an optimal time for cell delivery corresponding to this mechanism. Unfortunately, the results in the acute MI population have also been mixed. A related technique of injecting stem cells through the coronary artery wall into the peri-adventitial space using a very small gauge needle is under investigation by Penn and colleagues.2 This method may increase cell dwell time while still avoiding the risks of direct myocardial puncture.
For chronic ischemia, inta-myocardial injection has been the primary method of delivery. It affords longer dwell times and delivers the cells into the ischemic target zone more effectively than an intravascular option. While most studies using this method have shown positive results, the increases in ejection fraction and other metrics of left ventricular performance have been small. Symptomatic improvement has been more profound, but all studies to date have been small, making achievement of statistical significance difficult.
For non-ischemic cardiomyopathy, results have been mixed using either intravenous or intra-myocardial delivery methods, and there is less data. Tuma and colleagues, and others, have recently obtained encouraging results via a retrograde approach (Figure 1).3 This delivery method uses the femoral vein approach and injects cells into the coronary sinus using an occlusion balloon to prolong dwell time in the cardiac venous system. This retrograde method avoids complications involving the arterial tree and those associated with intra-myocardial injection. Further study will be necessary to see if the initial results can be reproduced in larger populations.
Stem cell delivery at the time of cardiac surgery via direct epicardial injection or through application of epicardial patches has shown similar results, but suffers from the invasive nature of an open chest procedure and the significantly increased costs. Results have shown modest improvement in left ventricular metrics and symptomatic relief.
The optimal delivery method and cell type remains an unanswered question for which further research is required. Hopefully, through further advances in our understanding of the biologic mechanisms of myocardial healing and the in the underlying mechanisms of stem cells, we will finally have a powerful tool in the fight against ischemic, and possibly non-ischemic, heart disease at the cellular and small vessel level.
Dr. Howard Walpole can be contacted at bowalpole@gmail.com
References
- Sanz-Ruiz R, Gutiérrez Ibañes E, Arranz AV, Fernández Santos ME, Fernández PL, Fernández-Avilés F. Phases I-III Clinical Trials Using Adult Stem Cells. Stem Cells Int. 2010 Nov 4; 2010: 579142. doi: 10.4061/2010/579142.
- Medicetty S, Wiktor D, Lehman N, Raber A, Popovic ZB, Deans R, Ting AE, Penn MS. Percutaneous adventitial delivery of allogeneic bone marrow-derived stem cells via infarct-related artery improves long-term ventricular function in acute myocardial infarction. Cell Transplant. 2012; 21(6): 1109-1120. doi: 10.3727/096368911X603657.
- Tuma J, Fernández-Viña R, Carrasco A, Castillo J, Cruz C, Carrillo A, et al. Safety and feasibility of percutaneous retrograde coronary sinus delivery of autologous bone marrow mononuclear cell transplantation in patients with chronic refractory angina. J Transl Med. 2011 Oct 26; 9: 183. doi: 10.1186/1479-5876-9-183.
