EXPLORING THE MODALITIES OF STEM CELL DELIVERY IN THE TREATMENT OF CARDIOVASCULAR DISEASES

Cardiovascular diseases remain the leading cause of death worldwide, claiming the lives of 17.9 million people annually, resulting in an estimated 32% of death globally. Most common cardiovascular-related deaths are caused by myocardial infarction, stroke and heart failure [1]. Death arising from cardiovascular diseases is commonly associated with irreparable damage to the cardiomyocytes, blood vessels or both, which may ultimately lead to heart failure [2]. The survival rate after diagnosis of heart failure is relatively low, with 24% of men (331) and 38% of women (321) surviving five years after diagnosis, indicating that the heart failure survival rate is lower than most types of cancers as seen in table 1 below [1,2].

PATHOLOGICAL CONDITION & FIVE-YEAR SURVIVAL RATE (AVERAGE)

Breast Cancer - 72%

Prostate Cancer - 55%

Colon Cancer - 42%

Heart Failure - 31%

Table 1: Table highlighting the five-year survival rate of some cancers compared to heart failure. [2]

Despite various pharmacological advancements in treating cardiovascular diseases over the last decade, the current most definitive cure for severe cardiovascular conditions like heart failure is heart transplantation [3]. However, the cost, complexity, limited availability of organs and complications of immunosuppressive therapies following transplantation impedes access to this form of intervention [3]. These medical limitations accompanied by the public health burden associated with cardiovascular diseases have sparked an interest in pursuing novel and more appropriate myocardial repair therapies.

Figure 1: A diagram of the Left ventricular assist device (LVAD) used as a temporary intervention before a heart transplant highlighting the complexity of the procedure. [3] Source: mayoclinic.org

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One of the most promising and innovative therapies is stem cell therapy. This regenerative procedure facilitates the repair response of dysfunctional and diseased tissue parts using stem cells such as embryonic stem cells, induced pluripotent cells and derivatives like cardiac stem cells, skeletal myoblast, mesenchymal and bone marrow-derived stem cells [4]. Pluripotent cells such as embryonic stem cells and induced pluripotent cells can differentiate into various cell types and are commonly used for cardiac regenerative therapy. For this purpose, they differentiate into cardiac progenitors or cardiomyocytes, which are utilized for myocardial repair [5]. Multipotent stem cells can differentiate into a group of cells in the same family, such as myoblasts, bone marrow-derived and mesenchymal stem cells, and resident cardiac stem cells, which are primarily utilized to restore heart functions. [6]. Stem cell therapy has proven to be theoretically effective in myocardial repair; however, the mechanism and modalities of cell delivery of the selected cell type in ensuring adequate engrafting of these cells into the myocardium face certain barriers. Cell delivery of stem cells is broadly classified into two types; local delivery and systemic delivery. Systemic delivery involves the intravenous release of the stem cell into the systemic circulation, whereas local delivery is specific and contained within the target organ [7]. Local delivery is preferred over systemic delivery because local delivery reduces the rate of venous flush out, leakage of the administered stem cells and the need for homing and mobilization of the transplanted stem cell. There are various local cell delivery modalities which include direct intramyocardial, intracoronary, and transendocardial as shown in figures 2a and 2b [7,8]?

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Figure 2a & 2b: Diagram highlighting the various systemic and local delivery modalities for stem cells [7,8] Source: sciencedirect.com

The direct intramyocardial approach is the current standard method of selective stem cell delivery into the infarcted area, and it is effective, precise and accurate. [7,8]. Before the procedure, the location of the myocardium can be identified using echocardiography or nuclear imaging; this facilitates precision and accuracy. The surgical procedure allows for empirical observations of the infarcted area. The direct intramyocardial injection can be done during invasive thoracotomies typical of open-heart surgery or via the less invasive lateral minithoracotomies that do not require induced cardiac arrest or perturbation of surrounding tissues and vasculature [9].

The most pressing drawback of direct intramyocardial injection is the potential to cause mechanical injury at the site of injection, which is followed by an inflammation that structurally disrupts the myocardium [7]. The formation of localized islets could lead to an increased risk of cardiac arrhythmias. The overall invasiveness of the procedure makes it risky and prevents limits the potential for multiple administrations [8]. The intracoronary method is a less invasive cell delivery method that has proven to be clinically effective; this procedure involves using a catheter to deliver the stem cells into the myocardium via the coronary artery. This route of administration is often preferred in patients following an acute myocardial infarction because the procedure can be done concurrently during a percutaneous coronary intervention to treat arterial stenosis [8]. The most significant advantage of intracoronary catheterization is that it allows for direct infusion into the specific target area, which results in homogeneous cell engraftment. The intracoronary route is less invasive than the intramyocardial route because it does not require a direct thoracotomy, preventing the accompanying complications and allowing the possibility of subsequent administration; this is an advantage it shares with the intravenous injection method, where a calculated dose of the stem cell is administered routinely via infusion into the systemic circulation [8].

Poor graft survival has been recorded in experiments using the intramyocardial route. In an experiment carried out by Fukushima et al., it was reported that less than 13% of the male-specific SRY-Positive cells were retained after three days and less than 1% after 28 days when administered using the intramyocardial injection method in female rats [10]. The poor retention can be attributed to certain factors such as leakage, environmental stress as a result of free radicals, rejection, inflammation and graft cell death, whether via apoptosis or necrosis [7,10]. The intracoronary injection is also faced with limited retention, where only a small portion is entrapped and extravasated into the myocardium, while the rest are subjected to venous flush out, which is a common denominator in all routes involving administration into blood vessels. There could also be the possibility of embolism in the blood vessels, hence the intracoronary method is not suitable for myocardial conditions associated with dysfunctional or damaged blood vessels [8].

While intramyocardial injection is target-specific, the intracoronary route is limited to highly vascularized areas, resulting in no supply to avascular areas. There is also a possibility of stem cells being starved, as blood contained in the coronary artery lacks oxygen and nutrients; all of this contributes to the poor survival and retention of administered stem cells [11].

Figure 3: Diagram highlighting the site specificity of the intramyocardial and intracoronary routes [11]. Source: Annals of Thoracic Surgery

The epicardial placement of stem cells is another method of transplantation that does not require catheterization or infusion. A bio-engineered cell sheet of hydrogel containing the donor stem cell is placed on the myocardium [12]. This method bypasses the limitations of both the intramyocardial and intracoronary methods, by ensuring the absence of embolism, arrhythmogenicity or direct myocardial damage [8]. According to Ichihara et al, an improved cardiac function was reported with an ejection fraction of 48% with the coating therapy compared to intramyocardial injection resulting in only 41% in rats with myocardial infarction [13]. The cell sheet is optimized with the temperature-responsive polymers as well as other modifications resulting in significant improvement in stem cell induction [12,13].

?The intramyocardial injection has proven to be effective; however, enhanced imaging and further research on the most effective dose and timing of administration will improve the rate of survival and myocardial repair.

It is also worth noting that, in this era of personalized medicines, the cell delivery method of choice should be the one that results in the best recovery and response for the patient based on the presenting conditions.

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REFERENCES

1. World Health Organization, Cardiovascular Disease Report. https://www.who.int/health-topics/cardiovascular-diseases [Accessed February 26, 2022]

2. Fuster, V. and Kelly, B. (2010). Epidemiology of Cardiovascular Diseases.

3. Russo, M., Iribarne A., Easterwood, R. et al (2010) "post-heart transplant survival is inferior at low-volume centres across all risk strata," Circulation, vol. 122, no. 11, supplement 1, pp. S85–S91.

4. Taylor, D., Atkins, B., Hungspreugs, P. et al (1998) “Regenerating functional myocardium: improved performance after?skeletal myoblast transplantation,”?Nature Medicine, vol. 4, no. 8, pp. 929–933.

5. Burridge, D., Keller, J., Gold, D. and Wu, J. (2012) “Production of de novo cardiomyocytes: human?pluripotent stem cell differentiation and direct reprogramming,”?Cell Stem Cell, vol. 10, no. 1, pp. 16–28.

6. Silva, G., Litovsky, J., Assad, A. et al (2005) “Mesenchymal stem cells differentiate into an endothelial phenotype, enhance vascular density, and improve?heart function in a canine chronic ischemia model,”?Circulation, vol. 111, no. 2, pp. 150–156.

7. Suzuki, K., Brand, N., Smolenski, R., et al (2000) “Development of a novel method for cell transplantation through the coronary artery” Circulation, vol. 102, pp. 359-364.

8. Sheng, C., Zhou, L., Hao, J et al (2013) “Current Stem Cell Delivery Methods for Myocardial Repair",?BioMed Research International,?vol.?2013,?Article ID?547902.

9. Patel, A., Geffner, R., Vina, F., et al (2005), Surgical treatment for congestive heart failure with autologous adult stem cell transplantation: a prospective randomized study,”?Journal of?Thoracic and Cardiovascular Surgery, vol. 130, no. 6, pp. 1631–1638.

10. Fukushima, S., Varela-Carver, A., Coppen, S., et al (2007) “Direct Intramyocardial But Not Intracoronary Injection of Bone Marrow Cells Induces Ventricular Arrhythmias in a Rat Chronic Ischemic Heart Failure Model” Circulation. 2007;115, pp 2254-2261.

11. Copland, B. (2011). “Mesenchymal stromal cells for cardiovascular disease,”?Journal of Cardiovascular Disease Research, vol. 2, no. 1, pp. 3–13.

12. Bel, A., Planet-Bernard, V., Saito, A., et al "Composite cell sheets: A further step toward safe and effective myocardial regeneration by cardiac progenitors derived from embryonic stem cells," Circulation, vol. 122, no. 11, supplement 1, pp. S118–S123.

13. Ichihara, Y., Kaneko, M., Yamagata, K. (2018) “Self-assembling peptide hydrogel enables instant epicardial coating of the heart with mesenchymal stromal cells for the treatment of heart failure” Biomaterials;154, pp: 12-23